What is included in activity based therapy, exactly? Also, patients have lives, so what is the minimum amount you must do in order to improve?
John MacDonald: ABRT is anything that combines the goal of increasing neurological activity AND combines it with physiological work. It's all about response over time. It's the whole range, including aquatherapy. It comes down to time constraints . . . how can you can get the biggest bang over time? Keep focused on doable goals, put the patient in a position where they have something to work on for about 8 hours a week.
Dr Nieshoff: it depends on what the patient is willing and able to do.
Dr. Hinderer: dose is still a big question. We based our own estimates on how much it takes to make neurological changes in the brain, because there is not functional mri for the cord yet; it's much harder to do that.
Q: I always come here to w2w, and I always leave so motivated . . but at home reality always intrudes. Work, family, school, bleh. How can I keep motivated.
Dr. MacDonald says that there's a ton of evidence that says if an AB gets 30 minutes of moderate physical activity per week, they're going to be healthier.
Dr Hinderer: We're not very sophisticated at the moment, and there of course is not insurance coverage . . . a clinical trial might be a way to get cost-free
Woman: I just became aware of a series of articles in the Spinal Cord Injury magazine about a wide study made to help gather data.
Meh. I raise my hand to suggest that we at u2fp set up an exercise support group. We have each other's contact information and we could make it a priority to get this done before we meet next year.
Friday, August 28, 2009
Panel with Dr MacDonald, Dr Hinderer, and Dr Nieshoff
Q: Dr MacDonald, you said that when you look at a patient's maximum function, that's what you work from . . . is there a way to know after a number of years where a patient is with precision?
The techniques are being developed to let us get at that. We rely on a careful clinical evaluation. The imaging doesn't tell about function; it's just showing anatomy. If you take a group of people who all have the same number of connections across, or the same mass of connections, they may all function differently. When we marry that kind of measurement to the progress in treatment, we learn a lot. It's an imperfect system, but getting better. It's even possible to get around the hardware problems, just takes a different protocol.
Q: Dr MacDonal, my son has an incomplete c5/6 injury and is doing therapy at SCI step. You scared me when you said that baclofen is detracting from his progress; he's thinking of getting a baclofen pump.
There's no doubt that you have to try to balance this, and that the benefits of baclofen can be important. I'd recommend that he get to a place where he can be fully evaluated . .. the answer is not to just go get a pump. DR Nieshoff jumps in to say that if the person is taking 400 mg a day, you have to ask why? Sometimes a period of gradual withdrawal and then gradual increase can get to the same reduced spasticity without that level of medication. Also I'd look at what might be causing the spasticity. I'd be loathe to consider a pump for a young person. Dr Hinderer says that several studies have been done to look at what can reduce the need for a pump. There are lots of things that reduce spasticity, but for an intracathal pump the FDA only approves baclofen.
Q: This is for both Steve and John. One of you just said that 2/3 of what we do in medicine is not evidence based. With FES, we have the luxury of not needing to amass more evidence, and there is a lot out there already to show that FES has many well-established health benefits. BUT, I do NOT think there is evidence anywhere to show that it causes axon regeneration and myelination. That's what your little cartoon seemed to claim. Comments?
John answers that it's clinically impossible to prove myelination, BUT with FES at the moment we're sort of at a dose-finding Phase II level of trial with spinal cord injury. Right now I advocate 3 hrs of FES, but that's based on the AB nervous system and has nothing to do with damaged CNS repair. Now it's time to do some animal models to look at what's happening at the molecular level. The technology is just beginning to catch up with that.
Dr. Kerr gets up to comment . . . Peter knows the answer to the question he just asked, because he's working on a trial with us that will try to see if FES is really needed, or if the same thing happens on a molecular level with just passive range of motion. From our trial, you can say that some people will recover and some won't. The question is what's the molecular fingerprint of repair. I think we're on the brink of understanding very clearly what FES can do.
Dr. Hinderer says that a challenge is finding something that is reproducible and reliable and also subject to change. It's important to look at methods other than what have traditionally been used; the ASIA scale is not very useful. The one Dr. McKay described yesterday is much more sensitive and something like that will definitely be important as we go forward.
Q: Has there been a look at more aggressive forms of rehab? Where is the health care debate going when it comes to the need for more and better?
Dr. MacDonald says that it's clear that we must have a way for a majority of people to access quality rehab. It will require emergent technology, using some kind of smart systems that let us know which of 20 factors is important. This is doable with thousands of patients, but it's not doable with hundreds. FES is good, but it's only about a third of what we do. Once people go home they have to be able to do it. We're going to need to demonstrate to the government that this works, and not just in reduction of complications. Dr. Nieshoff says that like it or not, we're one of the most expensive groups of patients to treat. We have to teach our legislators the difference between being penny wise and pound foolish.
Q: There's been a lot of talk about how we quantify motor control. It seems that Barry McKay's method is pretty good . . . do you know if this is going to become standard or if something else is?
Right now ASIA is the best we have; it's not very good but if you find someone who's good you'll get an accurate result.
Diaagreement - I think the ASIA scores are meaningless, and that there are quantitative measures of motor and sensory and autonomic function, which we ought to be pushing hard to get. It's not enough to say that ASIA is the best we have, so we have to go with it.
Can we do better? Certainly, but if we were in court that's what they'd go with. it is the standard.
Q: How do you detect subtle differences when they only have 5 levels?
When it's done by the book there's very little subjectivity involved. It's designed to be as objective as it can be. There are some components that are a little iffy, but right now this is the standard.
What you're talking about is scalability . . .one solution might be to increase the number of levels, like from 5 to 10 -- but better still would be to take out the examiner error.
Q: I'm a c4/5 hemiplegic. I was listening to you talk about the various things that have happened in rehab . . I want to back up what you have said about the need to get into exercise therapy. My question is about fatigue. If I cook a meal I have to go lie down because I'm so tired. If I walk for 6 minutes my Oxygen SAT goes down to 70.
You need a good onceover by a spinal cord doc. What you describe is things that can make a big difference in the way you function and in your own safety.
The end. On to the break, and then the breakout sessions. Woo hoo!
The techniques are being developed to let us get at that. We rely on a careful clinical evaluation. The imaging doesn't tell about function; it's just showing anatomy. If you take a group of people who all have the same number of connections across, or the same mass of connections, they may all function differently. When we marry that kind of measurement to the progress in treatment, we learn a lot. It's an imperfect system, but getting better. It's even possible to get around the hardware problems, just takes a different protocol.
Q: Dr MacDonal, my son has an incomplete c5/6 injury and is doing therapy at SCI step. You scared me when you said that baclofen is detracting from his progress; he's thinking of getting a baclofen pump.
There's no doubt that you have to try to balance this, and that the benefits of baclofen can be important. I'd recommend that he get to a place where he can be fully evaluated . .. the answer is not to just go get a pump. DR Nieshoff jumps in to say that if the person is taking 400 mg a day, you have to ask why? Sometimes a period of gradual withdrawal and then gradual increase can get to the same reduced spasticity without that level of medication. Also I'd look at what might be causing the spasticity. I'd be loathe to consider a pump for a young person. Dr Hinderer says that several studies have been done to look at what can reduce the need for a pump. There are lots of things that reduce spasticity, but for an intracathal pump the FDA only approves baclofen.
Q: This is for both Steve and John. One of you just said that 2/3 of what we do in medicine is not evidence based. With FES, we have the luxury of not needing to amass more evidence, and there is a lot out there already to show that FES has many well-established health benefits. BUT, I do NOT think there is evidence anywhere to show that it causes axon regeneration and myelination. That's what your little cartoon seemed to claim. Comments?
John answers that it's clinically impossible to prove myelination, BUT with FES at the moment we're sort of at a dose-finding Phase II level of trial with spinal cord injury. Right now I advocate 3 hrs of FES, but that's based on the AB nervous system and has nothing to do with damaged CNS repair. Now it's time to do some animal models to look at what's happening at the molecular level. The technology is just beginning to catch up with that.
Dr. Kerr gets up to comment . . . Peter knows the answer to the question he just asked, because he's working on a trial with us that will try to see if FES is really needed, or if the same thing happens on a molecular level with just passive range of motion. From our trial, you can say that some people will recover and some won't. The question is what's the molecular fingerprint of repair. I think we're on the brink of understanding very clearly what FES can do.
Dr. Hinderer says that a challenge is finding something that is reproducible and reliable and also subject to change. It's important to look at methods other than what have traditionally been used; the ASIA scale is not very useful. The one Dr. McKay described yesterday is much more sensitive and something like that will definitely be important as we go forward.
Q: Has there been a look at more aggressive forms of rehab? Where is the health care debate going when it comes to the need for more and better?
Dr. MacDonald says that it's clear that we must have a way for a majority of people to access quality rehab. It will require emergent technology, using some kind of smart systems that let us know which of 20 factors is important. This is doable with thousands of patients, but it's not doable with hundreds. FES is good, but it's only about a third of what we do. Once people go home they have to be able to do it. We're going to need to demonstrate to the government that this works, and not just in reduction of complications. Dr. Nieshoff says that like it or not, we're one of the most expensive groups of patients to treat. We have to teach our legislators the difference between being penny wise and pound foolish.
Q: There's been a lot of talk about how we quantify motor control. It seems that Barry McKay's method is pretty good . . . do you know if this is going to become standard or if something else is?
Right now ASIA is the best we have; it's not very good but if you find someone who's good you'll get an accurate result.
Diaagreement - I think the ASIA scores are meaningless, and that there are quantitative measures of motor and sensory and autonomic function, which we ought to be pushing hard to get. It's not enough to say that ASIA is the best we have, so we have to go with it.
Can we do better? Certainly, but if we were in court that's what they'd go with. it is the standard.
Q: How do you detect subtle differences when they only have 5 levels?
When it's done by the book there's very little subjectivity involved. It's designed to be as objective as it can be. There are some components that are a little iffy, but right now this is the standard.
What you're talking about is scalability . . .one solution might be to increase the number of levels, like from 5 to 10 -- but better still would be to take out the examiner error.
Q: I'm a c4/5 hemiplegic. I was listening to you talk about the various things that have happened in rehab . . I want to back up what you have said about the need to get into exercise therapy. My question is about fatigue. If I cook a meal I have to go lie down because I'm so tired. If I walk for 6 minutes my Oxygen SAT goes down to 70.
You need a good onceover by a spinal cord doc. What you describe is things that can make a big difference in the way you function and in your own safety.
The end. On to the break, and then the breakout sessions. Woo hoo!
Dr. Steven R. Hinderer
He's the medical director of Wal the LIne to SCI Recovery
Talk is called " How to Choose a Recovery Program"
I agree with Dr. MacDonald is that a cure is not needed to get to a lot of recovery of function . . . we only use about 10 to 20% of our physical capabilities to do everyday tasks, and a lot of people in this room would gladly take that much physical function.
Lots of medical pros will say that it's only okay to get involved in treatments that have been validated by clinical trials. But in 2001 -- 8 years ago -- only about a third of what goes on in medical practice was evidence based. What we're trying to do is change a paradigm. Innovation needs evolution and development BEFORE you can run clinical trials. It's a fact that evidence based treatments are not always best.
Showing a slide about the Wright Brothers, who endured countless failures and then decided that all the literature for wing design was wrong. They invented the wind tunnel so that they could test new ideas. We know how that worked out.
Okay, so what does the new paradigm look like? Start with FES, though it's not exactly new . . . it was applied for the first time to quadreplegics in 1967. Lots of advantages, and some disadvantages.
Nonresponders, can only vary the velocity, painful if you have sensation, risks fractures, muscles, or joint injuries, don't know the impact longterm of high intensity current (it's very different from nature) -- he thinks that it's a well-studied OLD technology . . .
For intact nervous systems, the small motor units are recruited first; well before teh small motor units reach their max firing rate, the midsized motor units are recruited, and well before they reach their max firign rate, the large motor units are recruited . . . but with FES, you go directly to the largest motor units, and there's no way to change that. FES therefore retrains the system somewhat backwards; it starts right at the large motor neurons, which is why it's so tiring.
What about weight supported training? In 1992, Wernig and Muller reported that body weight supported training, starting at 40%, improvd walking. It improved fitness, decreased spasticity, decreased contrctures, increased perceived well-being. There was also a study that showed BOTH weight supported gait training and over ground gait training resulted in improved walking.
Disadvantages of weight supported training: expensive, can only vary amount of weight supported and speed, doesn't include core runk muscles, must be able to tolerate upright position, onlyhelps with incomplete injuries.
His third alternative is load-bearing weight training. He's been setting us up for this one . . .
Paper by Giorgio Scivoletto . . . "The concept that restoration of a close to normal foot trajectory may be a very importnt goal of walking training and that this can be achieved provided the relative freedom of the other segments of hte lower limbs, trunk amd arms . . . " - anther paper to look up -- Here it is: http://nnr.sagepub.com/cgi/content/abstract/21/4/358
Okay, what are the principles that should be applied?
Repetition, repetition, repetition (with minor variations)
Nutrition and health maintenance
Core trunk strength and posture
Sensory inputs/integration
Dynamic coordination training
Activation of spinal cord motor nerve cells and the muscles to which they connect
Motivation to maximize performance
Mind-body connection
This is boot camp. You probably will have to have somebody like a coach or a therapist or a trainer . . . you're going to get sick of this damn quick. You need people to help you get your best game going every day.
Changes in neural pathways require
At least 3 hours per day
At least 3 days per week
More is better (within reason) -- some programs do 7 hours a day, 7 days a week.
Nutrition and health maintenance means
Hydration
Amino acids/proteins
Vitamin D
Adequate rest
What does core trunk strength and posture look like? He's got patients with better posture than a lot of AB people in the general population.
Sensory inputs -- this is interesting . . . vibration can either help or hurt. When it helps, it does so by improving bone density and stimulating sensory receptors.
Look at the Giger MD, made in Switzerland . . . http://www.gigermd.com/
How do you activate spinal motor nerves? full weight bearing, minimal use of orthotics, judicious use of localized FES (Bioness)
Know that this is years of work. It's Olympic level training, going for gold, and requires all the same kinds of support that an Olympic level athlete has to have.
Total Gym -- lots of sci exercise facilities use them.
Talk is called " How to Choose a Recovery Program"
I agree with Dr. MacDonald is that a cure is not needed to get to a lot of recovery of function . . . we only use about 10 to 20% of our physical capabilities to do everyday tasks, and a lot of people in this room would gladly take that much physical function.
Lots of medical pros will say that it's only okay to get involved in treatments that have been validated by clinical trials. But in 2001 -- 8 years ago -- only about a third of what goes on in medical practice was evidence based. What we're trying to do is change a paradigm. Innovation needs evolution and development BEFORE you can run clinical trials. It's a fact that evidence based treatments are not always best.
Showing a slide about the Wright Brothers, who endured countless failures and then decided that all the literature for wing design was wrong. They invented the wind tunnel so that they could test new ideas. We know how that worked out.
Okay, so what does the new paradigm look like? Start with FES, though it's not exactly new . . . it was applied for the first time to quadreplegics in 1967. Lots of advantages, and some disadvantages.
Nonresponders, can only vary the velocity, painful if you have sensation, risks fractures, muscles, or joint injuries, don't know the impact longterm of high intensity current (it's very different from nature) -- he thinks that it's a well-studied OLD technology . . .
For intact nervous systems, the small motor units are recruited first; well before teh small motor units reach their max firing rate, the midsized motor units are recruited, and well before they reach their max firign rate, the large motor units are recruited . . . but with FES, you go directly to the largest motor units, and there's no way to change that. FES therefore retrains the system somewhat backwards; it starts right at the large motor neurons, which is why it's so tiring.
What about weight supported training? In 1992, Wernig and Muller reported that body weight supported training, starting at 40%, improvd walking. It improved fitness, decreased spasticity, decreased contrctures, increased perceived well-being. There was also a study that showed BOTH weight supported gait training and over ground gait training resulted in improved walking.
Disadvantages of weight supported training: expensive, can only vary amount of weight supported and speed, doesn't include core runk muscles, must be able to tolerate upright position, onlyhelps with incomplete injuries.
His third alternative is load-bearing weight training. He's been setting us up for this one . . .
Paper by Giorgio Scivoletto . . . "The concept that restoration of a close to normal foot trajectory may be a very importnt goal of walking training and that this can be achieved provided the relative freedom of the other segments of hte lower limbs, trunk amd arms . . . " - anther paper to look up -- Here it is: http://nnr.sagepub.com/cgi/content/abstract/21/4/358
Okay, what are the principles that should be applied?
Repetition, repetition, repetition (with minor variations)
Nutrition and health maintenance
Core trunk strength and posture
Sensory inputs/integration
Dynamic coordination training
Activation of spinal cord motor nerve cells and the muscles to which they connect
Motivation to maximize performance
Mind-body connection
This is boot camp. You probably will have to have somebody like a coach or a therapist or a trainer . . . you're going to get sick of this damn quick. You need people to help you get your best game going every day.
Changes in neural pathways require
At least 3 hours per day
At least 3 days per week
More is better (within reason) -- some programs do 7 hours a day, 7 days a week.
Nutrition and health maintenance means
Hydration
Amino acids/proteins
Vitamin D
Adequate rest
What does core trunk strength and posture look like? He's got patients with better posture than a lot of AB people in the general population.
Sensory inputs -- this is interesting . . . vibration can either help or hurt. When it helps, it does so by improving bone density and stimulating sensory receptors.
Look at the Giger MD, made in Switzerland . . . http://www.gigermd.com/
How do you activate spinal motor nerves? full weight bearing, minimal use of orthotics, judicious use of localized FES (Bioness)
Know that this is years of work. It's Olympic level training, going for gold, and requires all the same kinds of support that an Olympic level athlete has to have.
Total Gym -- lots of sci exercise facilities use them.
Dr. John MacDonald
This is a relatively sophisticated audience, so I'm going to show a few more slides than I normally would . . . He works at the International Center for SCI. They focus on designing individualized, life-long in-home, restoration therapy rehabilitation program.
Talking points:
Most mechanisms of regeneration are activity-dependent
Micro-repair is sufficient for functional recovery
Delayed recovery is possible
Activity-based restoration therapies (ABRT) work
ABRT is important for meeting the cure half way
It requires more than just movement; you have to be focusing on muscle mass.
He's showing a conventional wisdom ASIA A slide . . . very depressing old set of thoughts, followed by a some images of injured cords. Says that the brain is organized differently from the cord. Puts Pat Rummerfield's cord up; clearly can see that he's got 30% of his cord left, and then asks Pat to stand up.
You don't need the whole cord. You have a lot redundancy, and the nervous system can deal with bad injuries if you give it half a chance.
We've done a series of studies in people with ASIA A, and the majority of them have 10 to 30% of their cords intact, and yet they don't have a lot of function. Why? We think that many of them have BAD information going through that remnant of a cord.
The goals for restoration therapy are:
Partial repair -- a full "cure" is not necessary to regain function.
Reduction of complications, like infection, skin breakdown, spasticity, fractures, DVT, pain, AD . . . 30% of people with sci have to go to the hospital at least once a year.
What do we do? What are regeneration strategies?
In order of level of difficulty: Optimize spontaneous regeneration, create bridges, reduce expression of inhibitory proteins, achieve neuronal cell birth and replacement, create appropriate re-connectivity and long tract regrowth.
The lowest hanging fruit is to make the most of spontaneous regeneration.
And it turns out that patterned neural acitvity is fundamental to development and regeneration. How can you tell if regeneration is happening? the indicators are cell birth, migration, myelination, and formation of circuits. Drugs like baclofen inhibit the nervous system, while FES stimulates it. The nervous system responds to lack of activity by increasing spasticity.
Describing an experiment in which they did a complete transection at T8/9 and put a chip into the rat's lower back that let them give her e-stim. They got a lot cell birth below the injury site, just as expected -- 70% more than in their control.
He's saying that the activity caused new cells to come into being. Similar study with dramatic proliferation of oligodendrocytes due to FES.
Showing what happens if you take baclofen . . . lowers population of both axons and oligodendrocytes. They also gave it to rats and then treated them with embryonic stem cells, and saw that fewer neurons were created.
video: Riding an FES bike for one hour is equivalent to walking 6,000 steps . .. I'm sure this is online.
Are there clinical studies of ABRT? Sure, more of them all the time. They all show that it reverses physical deterioration and has many other benefits.
Sadowsky et al, 2005 . . . I will look this up and post the link; John is showing the data, but too fast for me to type. The bottom line is that 70% of the people in the study got at least some function back, and 40% of them jumped a full level on the ASIA scale.
(having a little problem watching these slides because he keeps swinging the green fluorescent pointer wildly and quickly around the screen . . . giving me the spins)
Q: What about people who can't get to a center?
We have to set up a better system; what we need is to get beyond the walls.
Talking points:
Most mechanisms of regeneration are activity-dependent
Micro-repair is sufficient for functional recovery
Delayed recovery is possible
Activity-based restoration therapies (ABRT) work
ABRT is important for meeting the cure half way
It requires more than just movement; you have to be focusing on muscle mass.
He's showing a conventional wisdom ASIA A slide . . . very depressing old set of thoughts, followed by a some images of injured cords. Says that the brain is organized differently from the cord. Puts Pat Rummerfield's cord up; clearly can see that he's got 30% of his cord left, and then asks Pat to stand up.
You don't need the whole cord. You have a lot redundancy, and the nervous system can deal with bad injuries if you give it half a chance.
We've done a series of studies in people with ASIA A, and the majority of them have 10 to 30% of their cords intact, and yet they don't have a lot of function. Why? We think that many of them have BAD information going through that remnant of a cord.
The goals for restoration therapy are:
Partial repair -- a full "cure" is not necessary to regain function.
Reduction of complications, like infection, skin breakdown, spasticity, fractures, DVT, pain, AD . . . 30% of people with sci have to go to the hospital at least once a year.
What do we do? What are regeneration strategies?
In order of level of difficulty: Optimize spontaneous regeneration, create bridges, reduce expression of inhibitory proteins, achieve neuronal cell birth and replacement, create appropriate re-connectivity and long tract regrowth.
The lowest hanging fruit is to make the most of spontaneous regeneration.
And it turns out that patterned neural acitvity is fundamental to development and regeneration. How can you tell if regeneration is happening? the indicators are cell birth, migration, myelination, and formation of circuits. Drugs like baclofen inhibit the nervous system, while FES stimulates it. The nervous system responds to lack of activity by increasing spasticity.
Describing an experiment in which they did a complete transection at T8/9 and put a chip into the rat's lower back that let them give her e-stim. They got a lot cell birth below the injury site, just as expected -- 70% more than in their control.
He's saying that the activity caused new cells to come into being. Similar study with dramatic proliferation of oligodendrocytes due to FES.
Showing what happens if you take baclofen . . . lowers population of both axons and oligodendrocytes. They also gave it to rats and then treated them with embryonic stem cells, and saw that fewer neurons were created.
video: Riding an FES bike for one hour is equivalent to walking 6,000 steps . .. I'm sure this is online.
Are there clinical studies of ABRT? Sure, more of them all the time. They all show that it reverses physical deterioration and has many other benefits.
Sadowsky et al, 2005 . . . I will look this up and post the link; John is showing the data, but too fast for me to type. The bottom line is that 70% of the people in the study got at least some function back, and 40% of them jumped a full level on the ASIA scale.
(having a little problem watching these slides because he keeps swinging the green fluorescent pointer wildly and quickly around the screen . . . giving me the spins)
Q: What about people who can't get to a center?
We have to set up a better system; what we need is to get beyond the walls.
Anne Phipps, Co-founder Sci-Step Rehabilitation
Since 2002 I've been a T6 paraplegic and this is not my first w2w.
I'm honored to be here with you. In 2002 I was the marketing manager at my husband's Harley Davidson dealership . . . I loved it. I loved the speed and just being on the motorcycle.
Until Saturday august 10th 2002. I was up early after only a few of hours of restless sleep, getting ready to race. I sent into the burnout box and waited for the green light. I let go of the clutch and off I went. Halfway down the track I saw that my opponent wouldn't be able to catch me. As I crossed the finish line I tried to slow down and realized that something was wrong.
I spent the next few days in the hospital; I was airlifted to Craig Hospital. A woman I'd never met before informed me that I had been in a bad crash and that I was now paralyzed, for the rest of my life. She told me that my husband was out visiting rehab hospitals across the country to find the best place for me to go.
I passed out, and when I woke up, I heard the same thing all over again. I refused to believe it.
Every night I laid in bed wishing the nightmare would be over. When I woke up in the morning I was always sad to realize it was still going on. I didn't care what kind of chair I had. Part of my therapy involved being dumped out of my chair . . . the nurse asked me what I would do next. I reached for my cell phone to call my husband. She didn't laugh.
. . .
My husband found me a place to go in Texas, and the next trauma was to get onto the airplane. None of the attendants had a clue how to get me on . . . at the hotel we were given a handicapped room, but it was no way accessible. I went into an anxiety attack and wanted to go home. We got into an apartment and spent the next 2 weeks trying to modify what was not working, which was basically everything. The last thing on my mind was to do PT.
I remember spending 2 days doing nothing but trying to sit up and use a transfer board, getting so frustrated that I just wanted to go home. I made my husband drive me home to Ohio . . . we were so tired that neither of us had thought about the fact that I couldn't even get INTO my house, much less around it once I was in.
My husband and I started to fight all the time . . . he hired caregivers to help me around the clock. Eventually he found us a patio home that I could navigate; we were stuck with 2 houses for awhile.
through a friend about this time, I was introduced to Michelle Brock. We made a table and installed it at the Harley dealership, where I worked out for the next 2 months. It was a big distraction there, obviously, so we moved to another location . . . and in that location we realized that it would be good to offer this service to others in the sci community. We named it SCI STep, and in March of 2003 we enrolled our first client.
I felt for the first time that I was doing something with my life. About that time my husband and I chose to end the marriage, which had been damaged so badly during the last year.
The hardest part of my new life was needing to depend on an asssistant to help me do things . . . I set some goals for that year that would get me to independence and met every one of them.
But something wasn't right with my left hip and leg. At the hospital I found out that my left hip had been fractured in the crash and gone undiagnosed . . . the doctors told me to go be a good little paraplegic and forget about hip replacement surgery or ever walking again. Over the next year I had more than a dozen dislocations and 2 different prosthetics installed. This just meant to me that I had to find a way to walk without a hip.
I have a baclofen pump for spasticity. I've rolled over my own feet. It's a long list of speed bumps . . . but here I am. I live like I did before my injury. I never gave up on my recovery, even through the toughest of times. Even on the bad days, in the back of my mind, I took some strength from all the people who come to our facility.
That's why we offer a full free week to every person who wants to come to SCI step to try out what we have. A full week, free of charge. Everybody.
I do what I want now . .. I travel, I go to public events, I even date -- and have recently broken a few hearts.
SCI step is my life now. I've helped clients do so many things. We have clients who have tattooed our logo on their bodies. I've been involved in a lot of fundraisers, including a project that was about taking used wheelchair parts . . . I was able to help with an Extreme Home Makeover project.
(She thanks a long list of people . . . )
Serious WOW, people. What's above is not an exact transcription by any stretch, because Anne was talking a little fast. When we get the video up, I hope you all watch it over and over. She's truly awesome.
I'm honored to be here with you. In 2002 I was the marketing manager at my husband's Harley Davidson dealership . . . I loved it. I loved the speed and just being on the motorcycle.
Until Saturday august 10th 2002. I was up early after only a few of hours of restless sleep, getting ready to race. I sent into the burnout box and waited for the green light. I let go of the clutch and off I went. Halfway down the track I saw that my opponent wouldn't be able to catch me. As I crossed the finish line I tried to slow down and realized that something was wrong.
I spent the next few days in the hospital; I was airlifted to Craig Hospital. A woman I'd never met before informed me that I had been in a bad crash and that I was now paralyzed, for the rest of my life. She told me that my husband was out visiting rehab hospitals across the country to find the best place for me to go.
I passed out, and when I woke up, I heard the same thing all over again. I refused to believe it.
Every night I laid in bed wishing the nightmare would be over. When I woke up in the morning I was always sad to realize it was still going on. I didn't care what kind of chair I had. Part of my therapy involved being dumped out of my chair . . . the nurse asked me what I would do next. I reached for my cell phone to call my husband. She didn't laugh.
. . .
My husband found me a place to go in Texas, and the next trauma was to get onto the airplane. None of the attendants had a clue how to get me on . . . at the hotel we were given a handicapped room, but it was no way accessible. I went into an anxiety attack and wanted to go home. We got into an apartment and spent the next 2 weeks trying to modify what was not working, which was basically everything. The last thing on my mind was to do PT.
I remember spending 2 days doing nothing but trying to sit up and use a transfer board, getting so frustrated that I just wanted to go home. I made my husband drive me home to Ohio . . . we were so tired that neither of us had thought about the fact that I couldn't even get INTO my house, much less around it once I was in.
My husband and I started to fight all the time . . . he hired caregivers to help me around the clock. Eventually he found us a patio home that I could navigate; we were stuck with 2 houses for awhile.
through a friend about this time, I was introduced to Michelle Brock. We made a table and installed it at the Harley dealership, where I worked out for the next 2 months. It was a big distraction there, obviously, so we moved to another location . . . and in that location we realized that it would be good to offer this service to others in the sci community. We named it SCI STep, and in March of 2003 we enrolled our first client.
I felt for the first time that I was doing something with my life. About that time my husband and I chose to end the marriage, which had been damaged so badly during the last year.
The hardest part of my new life was needing to depend on an asssistant to help me do things . . . I set some goals for that year that would get me to independence and met every one of them.
But something wasn't right with my left hip and leg. At the hospital I found out that my left hip had been fractured in the crash and gone undiagnosed . . . the doctors told me to go be a good little paraplegic and forget about hip replacement surgery or ever walking again. Over the next year I had more than a dozen dislocations and 2 different prosthetics installed. This just meant to me that I had to find a way to walk without a hip.
I have a baclofen pump for spasticity. I've rolled over my own feet. It's a long list of speed bumps . . . but here I am. I live like I did before my injury. I never gave up on my recovery, even through the toughest of times. Even on the bad days, in the back of my mind, I took some strength from all the people who come to our facility.
That's why we offer a full free week to every person who wants to come to SCI step to try out what we have. A full week, free of charge. Everybody.
I do what I want now . .. I travel, I go to public events, I even date -- and have recently broken a few hearts.
SCI step is my life now. I've helped clients do so many things. We have clients who have tattooed our logo on their bodies. I've been involved in a lot of fundraisers, including a project that was about taking used wheelchair parts . . . I was able to help with an Extreme Home Makeover project.
(She thanks a long list of people . . . )
Serious WOW, people. What's above is not an exact transcription by any stretch, because Anne was talking a little fast. When we get the video up, I hope you all watch it over and over. She's truly awesome.
Aunt Marie!
I'm Sue's aunt. I'm a member of the local eagle's club, and we've been doing chicken fries for the last 2 years. You're only allowed to donate $25 at a time. You need to know that I'm the youngest person in this group, (laughs), and I just want to give u2fp this check for $500. It's a pittance, and doesn't go very far . . . but if we all do our part, we'll get somewhere.
(Need to say that I am personally just dead nuts about this woman. Thanks, Aunt Marie!)
(Need to say that I am personally just dead nuts about this woman. Thanks, Aunt Marie!)
Dr. Edward Nieshoff
Sue Maus introducing Dr. Edward Nieshoff from the Rehab Institute of MIchigan at U of M. Someone from this group has been with us every year since the beginning.
I want to show you how to make the most of intensive treatment; for the record I have financial support from the Pfizer institute.
Our strategy #1 is to figure out how to optimize muscle strength. Everybody knows that sci causes severe loss of muscle bulk, and there are often metabolic changes that cause rapid fatigue, especially in weight-bearing muscles.
One reason for this is that hormones change after sci . . . men lose a lot of testosterone, and many of them suffer from Low T syndrome. They have decreased energy, sex drive, energy -- but check with your doctor & find out if this is affecting you.
If you have low T, get some. If you don't, think about a hormone called oxandrolone. It's been studied in men with HIV, helping improve strength, endurance, sense of well being . . . also in a study of patients with burns, who had an average of 28% lower hospital stays. The results were so good that they stopped the trials early. The drug increases protein build up. Another doctor worked with patients how have decubitus ulcers and found benefit for them.
This drug is powerful but not necessarily benign . . . there are multiple potential side effects, including liver damage, hepatic tumors, lipid changes, acne, oily skin, mood changes, trouble sleeping, trouble urinating, breast swelling, prolonged erections, deepenng of the voice, unusual hair growth, allergic reactions.
If you choose to take it, you need regular liver testing to make sure you're not one of the small number of people who end up looking like the person on the screen -- a grossly over-steroided guy with bicps bigger than his head, and don't even get me started on the shoulders.
Strategy #2: optimize the heart function. When you first get an sci and then try to get out of bed you pass out. This gradually goes away over the first several months. Your blood pressure drops when you go from lying to sitting or from sitting to standing. There are some people who just can't tolerate getting into a standing frame, though, ever. There are also people who experience what they call exertional hypotension, which is getting very low blood pressure due to exercise.
If either of those is you, there is a drug called Midodrine that has been shown to improve activity tolerance and uprightness tolerance.
It also helps with exertional hypotension. There are quad athletes who do a thing called "clamping" -- which, yeeks! -- clamp off the foley to make their blood pressure go up. Apparently it works. It actually gives them a big performance bump, but is of course not very safe. Using midodrine does the same thing without the danger of dysreflexia.
Who should get midodrine? Someone who doesn't get relief from wearing a belly binder, because it's never a good idea to start with the drug. Potential side effects are AD, headache, gooseflesh, urinary retention, allergic retention. If you take it and then lie down, these things are more likely to happen.
Another drug: Clonidine
It's an old-fashioned drug that was originally developed to treat hypertension. It's similar to Zanaflex. Some people experience more side effects, some get more benefits. it can have a paradoxical hypertensive effect . . . in a normal person the blood pressure will drop with this drug, but in some people with sci, the drug raises the blood pressure. Sometimes it's used to treat drops in blood pressure with standing or walking.
Some studies (not controlled and rigorous) have shown that it helps a very significant percentage of people with sci who have spasticity.
Showing a slide that references a study by GUERTIN in 2009 that showed benefit of other drugs in walking, but not clonidine.
Basically with clonidine, it's a mixed bag. Some people experience it like fairy dust, some have a bad reaction, but the scientific community has not landed on any coherent explanation of why, in either case.
He concludes by saying that the optimal treatment means a comprehensive subspecialty care regime plus a good therapy program.
Very good stuff -- informative and clear.
I want to show you how to make the most of intensive treatment; for the record I have financial support from the Pfizer institute.
Our strategy #1 is to figure out how to optimize muscle strength. Everybody knows that sci causes severe loss of muscle bulk, and there are often metabolic changes that cause rapid fatigue, especially in weight-bearing muscles.
One reason for this is that hormones change after sci . . . men lose a lot of testosterone, and many of them suffer from Low T syndrome. They have decreased energy, sex drive, energy -- but check with your doctor & find out if this is affecting you.
If you have low T, get some. If you don't, think about a hormone called oxandrolone. It's been studied in men with HIV, helping improve strength, endurance, sense of well being . . . also in a study of patients with burns, who had an average of 28% lower hospital stays. The results were so good that they stopped the trials early. The drug increases protein build up. Another doctor worked with patients how have decubitus ulcers and found benefit for them.
This drug is powerful but not necessarily benign . . . there are multiple potential side effects, including liver damage, hepatic tumors, lipid changes, acne, oily skin, mood changes, trouble sleeping, trouble urinating, breast swelling, prolonged erections, deepenng of the voice, unusual hair growth, allergic reactions.
If you choose to take it, you need regular liver testing to make sure you're not one of the small number of people who end up looking like the person on the screen -- a grossly over-steroided guy with bicps bigger than his head, and don't even get me started on the shoulders.
Strategy #2: optimize the heart function. When you first get an sci and then try to get out of bed you pass out. This gradually goes away over the first several months. Your blood pressure drops when you go from lying to sitting or from sitting to standing. There are some people who just can't tolerate getting into a standing frame, though, ever. There are also people who experience what they call exertional hypotension, which is getting very low blood pressure due to exercise.
If either of those is you, there is a drug called Midodrine that has been shown to improve activity tolerance and uprightness tolerance.
It also helps with exertional hypotension. There are quad athletes who do a thing called "clamping" -- which, yeeks! -- clamp off the foley to make their blood pressure go up. Apparently it works. It actually gives them a big performance bump, but is of course not very safe. Using midodrine does the same thing without the danger of dysreflexia.
Who should get midodrine? Someone who doesn't get relief from wearing a belly binder, because it's never a good idea to start with the drug. Potential side effects are AD, headache, gooseflesh, urinary retention, allergic retention. If you take it and then lie down, these things are more likely to happen.
Another drug: Clonidine
It's an old-fashioned drug that was originally developed to treat hypertension. It's similar to Zanaflex. Some people experience more side effects, some get more benefits. it can have a paradoxical hypertensive effect . . . in a normal person the blood pressure will drop with this drug, but in some people with sci, the drug raises the blood pressure. Sometimes it's used to treat drops in blood pressure with standing or walking.
Some studies (not controlled and rigorous) have shown that it helps a very significant percentage of people with sci who have spasticity.
Showing a slide that references a study by GUERTIN in 2009 that showed benefit of other drugs in walking, but not clonidine.
Basically with clonidine, it's a mixed bag. Some people experience it like fairy dust, some have a bad reaction, but the scientific community has not landed on any coherent explanation of why, in either case.
He concludes by saying that the optimal treatment means a comprehensive subspecialty care regime plus a good therapy program.
Very good stuff -- informative and clear.
Wise Q and A
Do the patients need to be able weight bear alone for an hour?
No, just in a standing frame. Probably achievable for most patients.
What's the difference between the kind of rehab they do in China vs. the USA?
This has been the most intense debate we've had . . . in China every patient is pushed to the point of tolerance, which is obviously not the standard. Here we think that 1 hour a day for 3 days a week qualifies as intense. They've landed for the US trial on a standard of 3 hours per day for 3 days a week. All this will be walking, walking, walking. There is no data whatsoever on this subject. In Germany they did 3 hours a day for 5 days a week, which was considered at that time to be very intense.
Q: If you have a settlement, you're golden, if you're in the VA, you're silver, if you're neither, you're screwed . . . what's the plan to get people into these expensive trials?
There will be a lot of competition in the coming years. Money will be very tight. What the sci community can do is share the wealth. I see expensive equipment sitting in peoples' homes, and we should be making maximum use of these devices. There will be studies coming out that will justify insurance payment for these devices. It's hard, because it's a very tough question to answer.
Q: Will there be immunosuppression in your trials?
It won't be necessary, because we're matching blood in 4 out of 6 HLA categories. In our animal studies the cells do not get rejected.
Q: will the lithium cause pain?
Not in our studies. That was one of my primary worries; that lithium would cause pain. we just did an 80 patient study with a randomized placebo control . . . we will have a definitive answer this fall. we don't have any data on transplant plus lithium yet;
Q: Neurotrophins have been tried in the past and have not worked out very well
No, I have not seen that in humans . .
Lithium has been shown to stimulate stem cells in the brain as well as neurotrophins. It's been used for a century in treating the brain and the cord
Q: Will the patients have to live at the centers?
During the observational phase, people will have to be at the center 3 times. The patient doesn't have to come for the whole period. we anticipate a 3 day hospital stay, then they'll go home for 12 days, then come back for an intensive 6 week period of locomotor training. Some of the centers will be able to do more patients, but this has been the source of some very intense discussion, but we have not landed on any definitive answer.
Q: Who is going to pay for this?
We estimated that the total cost for this phase 3 trial would be $32 million. But we got the company to donate the cells, which brings it down to $24 million. Then on August 12 the FDA changed the rules so that we can recover some of the money from the patients; we're doing local fundraising, we're negotiating with the centers to lower the costs. We are committed to not having MONEY be the reason someone gets turned away.
We may do it like college admissions, where everyone who qualifies to be admitted is admitted, and then the potential to pay is factored into the cost for each person.
Q: What would probably be the expense after the trial to a patient?
We're carrying clinical trial insurance, so nothing. Remember that the trial will be randomized, so a quarter of the patients will get nothing, a quarter will get only lithium, a quarter will get only cord blood cells, and a quarter will get both. We have committed to giving all the participants the full treatment, assuming of course that the full treatment is effective.
In closing -- we should do this ourselves. I'm sick of waiting. We should not be waiting for a gift from a sugar daddy, or from the NIH, or from a company. I'm tired of waiting for someone who has a conflict of interest to step up. The people who have no conflict of interest in this -- who have in fact a vested interest in this -- are you.
www.justadollarplease.org
No, just in a standing frame. Probably achievable for most patients.
What's the difference between the kind of rehab they do in China vs. the USA?
This has been the most intense debate we've had . . . in China every patient is pushed to the point of tolerance, which is obviously not the standard. Here we think that 1 hour a day for 3 days a week qualifies as intense. They've landed for the US trial on a standard of 3 hours per day for 3 days a week. All this will be walking, walking, walking. There is no data whatsoever on this subject. In Germany they did 3 hours a day for 5 days a week, which was considered at that time to be very intense.
Q: If you have a settlement, you're golden, if you're in the VA, you're silver, if you're neither, you're screwed . . . what's the plan to get people into these expensive trials?
There will be a lot of competition in the coming years. Money will be very tight. What the sci community can do is share the wealth. I see expensive equipment sitting in peoples' homes, and we should be making maximum use of these devices. There will be studies coming out that will justify insurance payment for these devices. It's hard, because it's a very tough question to answer.
Q: Will there be immunosuppression in your trials?
It won't be necessary, because we're matching blood in 4 out of 6 HLA categories. In our animal studies the cells do not get rejected.
Q: will the lithium cause pain?
Not in our studies. That was one of my primary worries; that lithium would cause pain. we just did an 80 patient study with a randomized placebo control . . . we will have a definitive answer this fall. we don't have any data on transplant plus lithium yet;
Q: Neurotrophins have been tried in the past and have not worked out very well
No, I have not seen that in humans . .
Lithium has been shown to stimulate stem cells in the brain as well as neurotrophins. It's been used for a century in treating the brain and the cord
Q: Will the patients have to live at the centers?
During the observational phase, people will have to be at the center 3 times. The patient doesn't have to come for the whole period. we anticipate a 3 day hospital stay, then they'll go home for 12 days, then come back for an intensive 6 week period of locomotor training. Some of the centers will be able to do more patients, but this has been the source of some very intense discussion, but we have not landed on any definitive answer.
Q: Who is going to pay for this?
We estimated that the total cost for this phase 3 trial would be $32 million. But we got the company to donate the cells, which brings it down to $24 million. Then on August 12 the FDA changed the rules so that we can recover some of the money from the patients; we're doing local fundraising, we're negotiating with the centers to lower the costs. We are committed to not having MONEY be the reason someone gets turned away.
We may do it like college admissions, where everyone who qualifies to be admitted is admitted, and then the potential to pay is factored into the cost for each person.
Q: What would probably be the expense after the trial to a patient?
We're carrying clinical trial insurance, so nothing. Remember that the trial will be randomized, so a quarter of the patients will get nothing, a quarter will get only lithium, a quarter will get only cord blood cells, and a quarter will get both. We have committed to giving all the participants the full treatment, assuming of course that the full treatment is effective.
In closing -- we should do this ourselves. I'm sick of waiting. We should not be waiting for a gift from a sugar daddy, or from the NIH, or from a company. I'm tired of waiting for someone who has a conflict of interest to step up. The people who have no conflict of interest in this -- who have in fact a vested interest in this -- are you.
www.justadollarplease.org
Wise Young
Donna starts by asking if anybody in the room does not know Wise Young? No hands go up.
She talks about how important CareCure has been to all of us, and Wise's tireless advocacy and availability to people in chairs.
Wise takes the stage.
Thanks for this great meeting; organizers, you've hit another home run.
I've been asked to give a 101 on spinal cord injury. After yesterday's meeting I added a few slides. I'm going to talk about the barriers that this thing should address. I hope by the end of this, you'll feel as I do that this is not a never-never land. It's something we can conquer.
I want to bring up a couple of points. One is how tired I am of opening a newspaper and reading that someone will never walk again.
In the USA there are over a million spine injuries per year, but only 10% of them get a spinal cord injury, because we have this amazing protective system called the vertebrae. it only weighs a few pounds, which is astounding. It's been said that all of us will have back pain sooner or later . . . the pain we feel is meant to keep us from stressing that vertebrae system.
What's contusion? What's compression?
The great majority of sci's are caused by bone pressing into the cord. Contusion is when the bone presses rapidly into the cord . . .compression is when the bone presses slowly into the cord, cutting off the blood supply. The cord is more resilient than the brain. You can press on it for 20 minutes and it will still be okay; the brain gets damaged after 6.
Most injuries involve both. Early decompression after sci is critical; as recently as the 1980's neurosurgeons were saying there was no need to remove bone from damaged cords. That's how deep was the conviction that a damaged cord was not worth anything.
The cord is protected by the this membrane called the dura mater (tough mother); it floats in cerbrospinal fluid. The dura's job is to redistribute compressive forces; it's so tough that even with a very sharp knife you can barely cut through it.
The cord is stretchable -- it can be stretched by as much as 50% as long as you do it slowly. What's the speed at which axons break? half a meter per second.
Andy Blight did a study in the 80's that will never be replicated . . . contused the cords of cats and then went and counted the axons. What he found is that the myelinated axons were the weakest, because the little spaces between the bits of myelin wrapping are like weak spots in a chain of links.
Contusion damages large myelinated axons, and compression injury damages small unmyelinated axons.
Perfectly understandable image up of what a laminectomy does -- remove the bone that's near the cord. Showing sections of rat cords with injuries caused by dropping 10 grams onto them.
Secondary injury -- which people in the field did not even believe in 30 years ago -- is caused by calcium into neurons. Calcium rushes into injured neurons, and if the level of it is high enough, it will activate enzymes that kill the cell. At low levels calcium is just doing a job; at high levels it's toxic.
Methylprednisolone (think sylvester stillone for pronunciation) ... Wise gave a huge dose of the drug to patients -- a thousand times higher than was ever given before -- this was in 1981, and he says that if he asked permission from the FDA to do this today it would probably be denied. He couldn't sleep the night this was done, because many of his colleagues warned that he was going to kill these patients with such a high dose.
Okay, so should we really hate the secondary injury? Not exactly; it's there for a reason, and it's actually involved in tissue repair. Within 5 seconds after you contuse the cord, there are cytokines on the scene, and they're producing growth factors and calling for macrophages that remove toxins and myelin fragments that inhibit growth.
Talking about a colleague who uses staining to show that the cells that go to the injury site are coming from the bone marrow . . . their job is to rebuild blood vessels. There are also astrocytes that restore the blood brain barrier, which is a sort of field that protects our central nervous system. If you have a leaky blood brain barrier, you're one of the people who responds badly to certain Chinese food with a lot of glutamate.
Okay, what about the glial "scar" ? Astrocytes line the boundaries between the cns and the pns. These cells look at severely injured tissue and see it as foreign, meaning they see it as "outside" the central nervous system. Every week, he says, somebody on CC gets on to ask if they should have a surgeon cut out their scar . . . and every week he answers the same thing: you will get a worse scar if you do, because it's not really a physical scar. The act of "cutting" would introduce more astrocytes . . .
Image of chronic sci -- in this case a rat with an 18 week old injury. There are macrophages sitting right on the surviving part of the cord, eating up cells.
What about regrowth? Lots of vertebrates do have the ability to regrow their cords, like lamprey, zebrafish, tadpoles, newts, lizards . . . they're all short, less than 2 cm in diameter. Until around the time of world war II, people died from sci, so there was no time for evolution to work out a way to regrow human cords.
There are some tracts in human cord that do re-grow (sorry, missed the names, but the corticospinal cord was not one of them. But you knew that.)
The human cord has about 20 million axons; cats have about 500,000. Only 10% of the cord is needed for locomotion in rat, cat, and human. Most people with sci have 5 to 10% of their cord intact. This means that adding 5% of the axons is often enough for recovery. If you have a growing tumor in the cord, and it takes up 90% of the cord, you may not notice nothing.
There's a guy up on 76th street who cuts the thinnest slices of lox you can imagine; I've seen tumor removal patients who had thinner sections than that, and they walked out of the hospital. This made me believe early that if I only had to restore 5%, I could do it.
Graph up of percent of white matter sparing versus walking score . . . the 10% rule applies. If 10% of myelinated axons survive, the rats can walk.
Okay, what about the central pattern generator? Locomotion is programmed into the cord, which is why chickens with no heads can run.
Talking about a dancer named Carey who had only one patch of sensation on one leg; he was ASIA B and it took him 2 years to regain walking. He worked for Wise as a patient liaison who signed up every patient he visited to be in a study.
-------
What are the barriers to regeneration?
The injury site lacks certain cell adhesion milecules and is surrounded by reactive gliosis.
Time. Axons grow no faster than ahair, lesthan 1 mm per day. we need years of sustained growth.
Growth Inhibitors. Nogo and chondroitin 6 sulfate proteoglycans stop some axonal growth.
Effective regenerative therapies have to take on all three of these.
You put cells into the edge of the injury, not the center, where they can form a bridge. You put in growth factors that will help the cells to grow. And you put in antibodies to the inhibitors.
What kind of cells? Umbilical cord cells combined with lithium is what Wise has chosen to use, wow, he's speeding through his slides about the effects of lithium combined with umbilical cord blood.
When they announced these trials, and said they were being done in China, lots of Americans volunteered to go to China. Speed-talking, jeez, Wise.
The criteria for the US trials is:
Injury at least 1 year old,
OKAYYY. . . I have to get the final slides from him because he did the last 12 in about 1 minute. Or less. Posting now and making another post for the QA
She talks about how important CareCure has been to all of us, and Wise's tireless advocacy and availability to people in chairs.
Wise takes the stage.
Thanks for this great meeting; organizers, you've hit another home run.
I've been asked to give a 101 on spinal cord injury. After yesterday's meeting I added a few slides. I'm going to talk about the barriers that this thing should address. I hope by the end of this, you'll feel as I do that this is not a never-never land. It's something we can conquer.
I want to bring up a couple of points. One is how tired I am of opening a newspaper and reading that someone will never walk again.
In the USA there are over a million spine injuries per year, but only 10% of them get a spinal cord injury, because we have this amazing protective system called the vertebrae. it only weighs a few pounds, which is astounding. It's been said that all of us will have back pain sooner or later . . . the pain we feel is meant to keep us from stressing that vertebrae system.
What's contusion? What's compression?
The great majority of sci's are caused by bone pressing into the cord. Contusion is when the bone presses rapidly into the cord . . .compression is when the bone presses slowly into the cord, cutting off the blood supply. The cord is more resilient than the brain. You can press on it for 20 minutes and it will still be okay; the brain gets damaged after 6.
Most injuries involve both. Early decompression after sci is critical; as recently as the 1980's neurosurgeons were saying there was no need to remove bone from damaged cords. That's how deep was the conviction that a damaged cord was not worth anything.
The cord is protected by the this membrane called the dura mater (tough mother); it floats in cerbrospinal fluid. The dura's job is to redistribute compressive forces; it's so tough that even with a very sharp knife you can barely cut through it.
The cord is stretchable -- it can be stretched by as much as 50% as long as you do it slowly. What's the speed at which axons break? half a meter per second.
Andy Blight did a study in the 80's that will never be replicated . . . contused the cords of cats and then went and counted the axons. What he found is that the myelinated axons were the weakest, because the little spaces between the bits of myelin wrapping are like weak spots in a chain of links.
Contusion damages large myelinated axons, and compression injury damages small unmyelinated axons.
Perfectly understandable image up of what a laminectomy does -- remove the bone that's near the cord. Showing sections of rat cords with injuries caused by dropping 10 grams onto them.
Secondary injury -- which people in the field did not even believe in 30 years ago -- is caused by calcium into neurons. Calcium rushes into injured neurons, and if the level of it is high enough, it will activate enzymes that kill the cell. At low levels calcium is just doing a job; at high levels it's toxic.
Methylprednisolone (think sylvester stillone for pronunciation) ... Wise gave a huge dose of the drug to patients -- a thousand times higher than was ever given before -- this was in 1981, and he says that if he asked permission from the FDA to do this today it would probably be denied. He couldn't sleep the night this was done, because many of his colleagues warned that he was going to kill these patients with such a high dose.
Okay, so should we really hate the secondary injury? Not exactly; it's there for a reason, and it's actually involved in tissue repair. Within 5 seconds after you contuse the cord, there are cytokines on the scene, and they're producing growth factors and calling for macrophages that remove toxins and myelin fragments that inhibit growth.
Talking about a colleague who uses staining to show that the cells that go to the injury site are coming from the bone marrow . . . their job is to rebuild blood vessels. There are also astrocytes that restore the blood brain barrier, which is a sort of field that protects our central nervous system. If you have a leaky blood brain barrier, you're one of the people who responds badly to certain Chinese food with a lot of glutamate.
Okay, what about the glial "scar" ? Astrocytes line the boundaries between the cns and the pns. These cells look at severely injured tissue and see it as foreign, meaning they see it as "outside" the central nervous system. Every week, he says, somebody on CC gets on to ask if they should have a surgeon cut out their scar . . . and every week he answers the same thing: you will get a worse scar if you do, because it's not really a physical scar. The act of "cutting" would introduce more astrocytes . . .
Image of chronic sci -- in this case a rat with an 18 week old injury. There are macrophages sitting right on the surviving part of the cord, eating up cells.
What about regrowth? Lots of vertebrates do have the ability to regrow their cords, like lamprey, zebrafish, tadpoles, newts, lizards . . . they're all short, less than 2 cm in diameter. Until around the time of world war II, people died from sci, so there was no time for evolution to work out a way to regrow human cords.
There are some tracts in human cord that do re-grow (sorry, missed the names, but the corticospinal cord was not one of them. But you knew that.)
The human cord has about 20 million axons; cats have about 500,000. Only 10% of the cord is needed for locomotion in rat, cat, and human. Most people with sci have 5 to 10% of their cord intact. This means that adding 5% of the axons is often enough for recovery. If you have a growing tumor in the cord, and it takes up 90% of the cord, you may not notice nothing.
There's a guy up on 76th street who cuts the thinnest slices of lox you can imagine; I've seen tumor removal patients who had thinner sections than that, and they walked out of the hospital. This made me believe early that if I only had to restore 5%, I could do it.
Graph up of percent of white matter sparing versus walking score . . . the 10% rule applies. If 10% of myelinated axons survive, the rats can walk.
Okay, what about the central pattern generator? Locomotion is programmed into the cord, which is why chickens with no heads can run.
Talking about a dancer named Carey who had only one patch of sensation on one leg; he was ASIA B and it took him 2 years to regain walking. He worked for Wise as a patient liaison who signed up every patient he visited to be in a study.
-------
What are the barriers to regeneration?
The injury site lacks certain cell adhesion milecules and is surrounded by reactive gliosis.
Time. Axons grow no faster than ahair, lesthan 1 mm per day. we need years of sustained growth.
Growth Inhibitors. Nogo and chondroitin 6 sulfate proteoglycans stop some axonal growth.
Effective regenerative therapies have to take on all three of these.
You put cells into the edge of the injury, not the center, where they can form a bridge. You put in growth factors that will help the cells to grow. And you put in antibodies to the inhibitors.
What kind of cells? Umbilical cord cells combined with lithium is what Wise has chosen to use, wow, he's speeding through his slides about the effects of lithium combined with umbilical cord blood.
When they announced these trials, and said they were being done in China, lots of Americans volunteered to go to China. Speed-talking, jeez, Wise.
The criteria for the US trials is:
Injury at least 1 year old,
OKAYYY. . . I have to get the final slides from him because he did the last 12 in about 1 minute. Or less. Posting now and making another post for the QA
Friday morning: Marilyn Smith & Rachel Hammerman
Marilyn is at the podium talking about the agenda for today; unfortunate news is that Phil Horner will not be giving his presentation here today because of a family emergency.
The good news about that is that we get a little more time for lunch, a little more time for the presentations we do have.
Now . . what's u2fp anyway? Not a fundraising organization, just a group of people connected to sci in some way who wanted to step up and become the voice of the community. We see our job as
She introduces our public policy liaison, Rachel Hammerman, who helped us get the CDRPA passed.
Rachel is young and beautiful, standing at the microphone explaining that she's going to talk about speaking up and being visible. "Raise your hand of if you can't raise your hand have your neighbor raise two hands . . . " Almost everyone does.
So what does it mean to be an advocate? Woman says that for her it was speaking up and asking that her son get what he needs. Todd says that the most powerful thing is how you appeal to someone's emotions. Stephen Davies says that he tries to come up with effective therapies, and speaks with politicians and with the media about the fact that the research is getting somewhere. Sue Maus says that last year on Capitol hill Stephen had a 102 fever and went to the congressional briefing anyway, then agreed to go to Norm Coleman's office . . . Coleman wanted to hear from him: "Where is the science? How close are we?" She says that Stephen's presence was key to getting that vote.
Rachel: that bill was on the floor for 7 years. We were up there for 4 of those years, and if you were on our mailing list, you got those emails, you made those calls.
Advocacy means speaking out on our own behalf or on behalf of others -- what we're doing is helping people become passionate about research and cures.
If someone asks you what you did this week, you can tell them: I was learning about research for sci. That's advocacy.
What forms can advocacy take? Just about anything . . . for some people it's clicking that button when you get an email, for some it's public speaking, for some it's just talking with your neighbors. It's NOT keeping your mouth shut.
The key is persistence, and obviously every person in this room knows what that word means . . .
So, she's going to go through a list w/ more detail. Suggests that people use the blog link to show others what this conference was about. The big goal is to show others what this is. Use all the social networks you have, like facebook -- put it on your status. "I was at w2w in chicago."
Then there's the media advocate . .. before you get to that, you need a 15 second elevator pitch -- a sentence that can be said in the time it takes to ride in an elevator.
Media includes everything from old-fashioned newspapers to twitter. Yesterday Naomi Kleitman said yesterday that she was quoted in the media as saying "I don't think there's going to be a cure" when what she said was "I don't think there's going to be one single cure, it's going to be more of a combination." So, be careful.
Sean Tipton, who led the fight on Capitol Hill to pass funding for ESCR, says that you must have 4 talking points, and use the image of a prism to help you stay on them. The question comes through the tip of the prism . . . your job is to direct that question to one of the 4 faces of the prism-- your talking points. Never, ever leave them.
All of us, she says, are BOSSES in the sense that each of us has 4 employees: our representatives in congress (2 senators and 1 representative, plus the president). You're free to call them up, write to them, get their attention. The person you'll usually work with is the Health Legislative Assistant. You'll probably get their voicemail. You almost NEVER get to speak with them right away. This is where you must be persistent . .. eventually will get to speak with them.
This is why it matters so much to have some talking points -- faces of the prism -- all ready. Go ahead and use what's on the u2fp website; that's what it's there for.
Talks about the wonderful Donna Sullivan, who put the phone numbers of her own representatives in Ohio into her speed dial and called them every day until she got their attention. They all signed on to CDRPA.
No matter what your own strengths and weaknesses are, you can make a difference. Talk about why this matters so much, wherever you are.
The whole reason u2fp exists is to give each of you a LOT of ways to advocate. Call us, email us, read your handouts.
Joe White is talking about being in the Mall of America, and how he always carries cards with him . . . if someone asks a question ("How do you like your chair?") I give them a card and explain what it means.
Todd says that people should remember that the legislative office people you usually talk with are very young, and they'll be moving up the ranks; now's an easy to time educate them and motivate them to help when they have more authority. Make relationships now.
Joe says that people should call the newspapers when we get home to describe this event. You might get a little blurb, but every bit of exposure helps.
RAchel signs off, and Marilyn is back to say that although u2fp is not a fundraising organization, we do recognize that sci research is deeply underfunded, and that many people here are interested in how to do this.
The website and the materials we handed out at registration have a fundraising kit that has some guidelines about how to do this. Joe White has staged a Walk and Roll fundraiser in his home town . . . he explains:
We got together a couple of years ago . . . I left working2walk a few years ago and decided that I needed to do something. We rented a pavilion and got some local businesses to donate the cost of that, plus t shirts and food and flyers. I thought we might get 20 people who donated 100 dollars. We got 120 people and raised 16 Thousand dollars. Gave some to u2fp and some to Dr. Davies and kept some seed money for the next one. Our 3rd annual event is this October.
Marilyn: anybody who's ever done anything like this will tell you that it's a lot of fun. Image is up of Karen Miner's group, Research for Cure, which has raised $340,000 for Hans Keirstead's lab in Irvine over the last decade or so.
Okay, so what if you don't have the time or interest to organize a fundraiser? There are ways to participate . . . we know of a few people who did the Rock and Roll marathon, or the Team Reeve marathon and raised money through them.
There are also matching gift programs that many employers use. And, think about micro-funding. You don't need to go raise $500,000 . . . you can raise $5 from 100,000 people, or from 50 people. Whatever. It all helps, and whatever you do, even the old tried and true things like car washes and bake sales, is using what you have to make a difference.
Woman is describing how after her son's best friend was injured in a crash 16 years, her daughter had the idea of raising money through a car wash and bake sale -- that was a success and it grew into a statewide organization.
Image of Jennifer Longdon, who did the Rock and Roll marathon in Phoenix and raised a pile of money for the Keirstead lab.
Marilyn describes a Chicago guy who was here earlier but had to work -- 2 year old injury and dove right into fundraising. Has so far raised $100,000.
Turns it over to Donna, who will introduce Wise.
The good news about that is that we get a little more time for lunch, a little more time for the presentations we do have.
Now . . what's u2fp anyway? Not a fundraising organization, just a group of people connected to sci in some way who wanted to step up and become the voice of the community. We see our job as
She introduces our public policy liaison, Rachel Hammerman, who helped us get the CDRPA passed.
Rachel is young and beautiful, standing at the microphone explaining that she's going to talk about speaking up and being visible. "Raise your hand of if you can't raise your hand have your neighbor raise two hands . . . " Almost everyone does.
So what does it mean to be an advocate? Woman says that for her it was speaking up and asking that her son get what he needs. Todd says that the most powerful thing is how you appeal to someone's emotions. Stephen Davies says that he tries to come up with effective therapies, and speaks with politicians and with the media about the fact that the research is getting somewhere. Sue Maus says that last year on Capitol hill Stephen had a 102 fever and went to the congressional briefing anyway, then agreed to go to Norm Coleman's office . . . Coleman wanted to hear from him: "Where is the science? How close are we?" She says that Stephen's presence was key to getting that vote.
Rachel: that bill was on the floor for 7 years. We were up there for 4 of those years, and if you were on our mailing list, you got those emails, you made those calls.
Advocacy means speaking out on our own behalf or on behalf of others -- what we're doing is helping people become passionate about research and cures.
If someone asks you what you did this week, you can tell them: I was learning about research for sci. That's advocacy.
What forms can advocacy take? Just about anything . . . for some people it's clicking that button when you get an email, for some it's public speaking, for some it's just talking with your neighbors. It's NOT keeping your mouth shut.
The key is persistence, and obviously every person in this room knows what that word means . . .
So, she's going to go through a list w/ more detail. Suggests that people use the blog link to show others what this conference was about. The big goal is to show others what this is. Use all the social networks you have, like facebook -- put it on your status. "I was at w2w in chicago."
Then there's the media advocate . .. before you get to that, you need a 15 second elevator pitch -- a sentence that can be said in the time it takes to ride in an elevator.
Media includes everything from old-fashioned newspapers to twitter. Yesterday Naomi Kleitman said yesterday that she was quoted in the media as saying "I don't think there's going to be a cure" when what she said was "I don't think there's going to be one single cure, it's going to be more of a combination." So, be careful.
Sean Tipton, who led the fight on Capitol Hill to pass funding for ESCR, says that you must have 4 talking points, and use the image of a prism to help you stay on them. The question comes through the tip of the prism . . . your job is to direct that question to one of the 4 faces of the prism-- your talking points. Never, ever leave them.
All of us, she says, are BOSSES in the sense that each of us has 4 employees: our representatives in congress (2 senators and 1 representative, plus the president). You're free to call them up, write to them, get their attention. The person you'll usually work with is the Health Legislative Assistant. You'll probably get their voicemail. You almost NEVER get to speak with them right away. This is where you must be persistent . .. eventually will get to speak with them.
This is why it matters so much to have some talking points -- faces of the prism -- all ready. Go ahead and use what's on the u2fp website; that's what it's there for.
Talks about the wonderful Donna Sullivan, who put the phone numbers of her own representatives in Ohio into her speed dial and called them every day until she got their attention. They all signed on to CDRPA.
No matter what your own strengths and weaknesses are, you can make a difference. Talk about why this matters so much, wherever you are.
The whole reason u2fp exists is to give each of you a LOT of ways to advocate. Call us, email us, read your handouts.
Joe White is talking about being in the Mall of America, and how he always carries cards with him . . . if someone asks a question ("How do you like your chair?") I give them a card and explain what it means.
Todd says that people should remember that the legislative office people you usually talk with are very young, and they'll be moving up the ranks; now's an easy to time educate them and motivate them to help when they have more authority. Make relationships now.
Joe says that people should call the newspapers when we get home to describe this event. You might get a little blurb, but every bit of exposure helps.
RAchel signs off, and Marilyn is back to say that although u2fp is not a fundraising organization, we do recognize that sci research is deeply underfunded, and that many people here are interested in how to do this.
The website and the materials we handed out at registration have a fundraising kit that has some guidelines about how to do this. Joe White has staged a Walk and Roll fundraiser in his home town . . . he explains:
We got together a couple of years ago . . . I left working2walk a few years ago and decided that I needed to do something. We rented a pavilion and got some local businesses to donate the cost of that, plus t shirts and food and flyers. I thought we might get 20 people who donated 100 dollars. We got 120 people and raised 16 Thousand dollars. Gave some to u2fp and some to Dr. Davies and kept some seed money for the next one. Our 3rd annual event is this October.
Marilyn: anybody who's ever done anything like this will tell you that it's a lot of fun. Image is up of Karen Miner's group, Research for Cure, which has raised $340,000 for Hans Keirstead's lab in Irvine over the last decade or so.
Okay, so what if you don't have the time or interest to organize a fundraiser? There are ways to participate . . . we know of a few people who did the Rock and Roll marathon, or the Team Reeve marathon and raised money through them.
There are also matching gift programs that many employers use. And, think about micro-funding. You don't need to go raise $500,000 . . . you can raise $5 from 100,000 people, or from 50 people. Whatever. It all helps, and whatever you do, even the old tried and true things like car washes and bake sales, is using what you have to make a difference.
Woman is describing how after her son's best friend was injured in a crash 16 years, her daughter had the idea of raising money through a car wash and bake sale -- that was a success and it grew into a statewide organization.
Image of Jennifer Longdon, who did the Rock and Roll marathon in Phoenix and raised a pile of money for the Keirstead lab.
Marilyn describes a Chicago guy who was here earlier but had to work -- 2 year old injury and dove right into fundraising. Has so far raised $100,000.
Turns it over to Donna, who will introduce Wise.
Thursday, August 27, 2009
Panel: Naomi Kleitman, Barry McKay, Peter Gorman, and Tony Caggiano
Tony is speaking about his role as manager of the clinical trial process at Acorda.
Naomi asks if people were in clinical trials, and several explain what they were involved in.
One did the fampridine trial and is eagerly waiting for the release of the drug next fall. One used a device that was not yet approved, but the company that was manufacturing it went under. She now gets it from England at a very high cost. The panel says that it's a big issue; companies go under and there you are. A couple of people went to Gainesville for the suspended gait training, and both got benefit.
Naomi wants to know if any minds were changed today about the lack of clinical trials ~ nobody answers her question, but someone asks another one about the 4sci trials. It seems to be about repeating animal tests that seemed promising. Theyve now repeated about a dozen of these trials and so far failed to replicate what was published.
(This sucks, of course, but here's how finely tuned the spinal cord is . . .when they tried to replicate studies from Europe, one issue was that the strain of the animals being tested was a little different in the USA. Small physiological change => different outcome.)
Man in the front row is asking about off-label usage of approved drugs. They tell him that doctors are free to prescribe drugs . . . but does the NIH care about this? Naomi says that there are 26 funding centers at the NIH. The entry criteria for getting money from NIH is about a million $ a year.
Ida Cahill says that she gets phone calls from people who are thinking of going outside the USA. She knows of 2 women who went to Portugal, and 2 more who went to India. They spent $70k each plus travel to go get who knows what done to them.
Some talk about this, and how to know if a trial is legit. Basically, it's just a very risky undertaking to leave the country, especially if the therapy you're getting involves cells. Naomi gets up to talk about what red flags look like, refers people again to the iCord website where the full question set is available.
Man asks about the existence of a national database . . . if you get cancer your name automatically gets put into a giant list that keeps track of everyone; the answer is that hiipa regulations prevent this from being done -- that can't be right, can it? Then why do cancer patients do it?
A question about emergencies -- how the heck to doctors and scientists go about inviting people with new injuries (who are devastated physically and personally) to give their consent to a trial. Naomi is describing something called community consent that made it possible to include minorities, who as it turned out, were being underserved.
A question about whether or not the trials that involve cells are going to have controls. The answer is no, at least not in Phase I. What will happen in Phase II?
In some studies (ProChord) they've hidden the information from the evaluators. It's always a tension between the need to do the science right and the need to treat patients ethically.
Woman says that the VA hospitals are looking for study subjects.
Man says that the Portugal trial has been through the EU version of the FDA, and that an IRB does exist there, and at least one paper has been published about the results. He's a rehab doctor at Wayne state university. Panel member replies that the paper had flawed data, as would be clear to anybody with a statistical background. He says they also have claimed no adverse effects, but he personally knows of 6 very adverse effects. He's worked with people who got the Lisbon treatment, came back for intense PT and compared them with people who just got the PT . . . no difference. NADA.
Another panelist says that, you know, here we are with 2 qualified people looking at the same data and coming to a different conclusion. (That is what I hate.)
Woman whose daughter has been injured for 18 years says that she's seen rats walking, for heaven's sake. How on earth do you all come together? Panelist says that his favorite annual meeting is the ASIA meeting. They do learn from one another there. Also the journal Spinal Cord Injury. Also the peer review process. Also the NIH funding process itself, which is a marker to show that this work is new, promising, and original.
Woman asks the assessment measures guy what's being done with his work . . . he says that it will let small changes be documented and approaches be validated.
She says, could this assessment tool be used to convince insurance companies to pay for treatments like rehab?
He says he can't imagine that it wouldn't . . . and people should understand that to bring a group of combined treatments to the FDA -- oh, wait. Naomi says all they need is to show that their is safety in each of the individual components.
Oy, long day, people. Marilyn says it's time for a little socializing. Yay! Plus we get a buffet -- a Mexican buffet! Woo hoo, seriously.
Naomi asks if people were in clinical trials, and several explain what they were involved in.
One did the fampridine trial and is eagerly waiting for the release of the drug next fall. One used a device that was not yet approved, but the company that was manufacturing it went under. She now gets it from England at a very high cost. The panel says that it's a big issue; companies go under and there you are. A couple of people went to Gainesville for the suspended gait training, and both got benefit.
Naomi wants to know if any minds were changed today about the lack of clinical trials ~ nobody answers her question, but someone asks another one about the 4sci trials. It seems to be about repeating animal tests that seemed promising. Theyve now repeated about a dozen of these trials and so far failed to replicate what was published.
(This sucks, of course, but here's how finely tuned the spinal cord is . . .when they tried to replicate studies from Europe, one issue was that the strain of the animals being tested was a little different in the USA. Small physiological change => different outcome.)
Man in the front row is asking about off-label usage of approved drugs. They tell him that doctors are free to prescribe drugs . . . but does the NIH care about this? Naomi says that there are 26 funding centers at the NIH. The entry criteria for getting money from NIH is about a million $ a year.
Ida Cahill says that she gets phone calls from people who are thinking of going outside the USA. She knows of 2 women who went to Portugal, and 2 more who went to India. They spent $70k each plus travel to go get who knows what done to them.
Some talk about this, and how to know if a trial is legit. Basically, it's just a very risky undertaking to leave the country, especially if the therapy you're getting involves cells. Naomi gets up to talk about what red flags look like, refers people again to the iCord website where the full question set is available.
Man asks about the existence of a national database . . . if you get cancer your name automatically gets put into a giant list that keeps track of everyone; the answer is that hiipa regulations prevent this from being done -- that can't be right, can it? Then why do cancer patients do it?
A question about emergencies -- how the heck to doctors and scientists go about inviting people with new injuries (who are devastated physically and personally) to give their consent to a trial. Naomi is describing something called community consent that made it possible to include minorities, who as it turned out, were being underserved.
A question about whether or not the trials that involve cells are going to have controls. The answer is no, at least not in Phase I. What will happen in Phase II?
In some studies (ProChord) they've hidden the information from the evaluators. It's always a tension between the need to do the science right and the need to treat patients ethically.
Woman says that the VA hospitals are looking for study subjects.
Man says that the Portugal trial has been through the EU version of the FDA, and that an IRB does exist there, and at least one paper has been published about the results. He's a rehab doctor at Wayne state university. Panel member replies that the paper had flawed data, as would be clear to anybody with a statistical background. He says they also have claimed no adverse effects, but he personally knows of 6 very adverse effects. He's worked with people who got the Lisbon treatment, came back for intense PT and compared them with people who just got the PT . . . no difference. NADA.
Another panelist says that, you know, here we are with 2 qualified people looking at the same data and coming to a different conclusion. (That is what I hate.)
Woman whose daughter has been injured for 18 years says that she's seen rats walking, for heaven's sake. How on earth do you all come together? Panelist says that his favorite annual meeting is the ASIA meeting. They do learn from one another there. Also the journal Spinal Cord Injury. Also the peer review process. Also the NIH funding process itself, which is a marker to show that this work is new, promising, and original.
Woman asks the assessment measures guy what's being done with his work . . . he says that it will let small changes be documented and approaches be validated.
She says, could this assessment tool be used to convince insurance companies to pay for treatments like rehab?
He says he can't imagine that it wouldn't . . . and people should understand that to bring a group of combined treatments to the FDA -- oh, wait. Naomi says all they need is to show that their is safety in each of the individual components.
Oy, long day, people. Marilyn says it's time for a little socializing. Yay! Plus we get a buffet -- a Mexican buffet! Woo hoo, seriously.
Peter Gorman, University of Maryland
Sorry, I missed some information trying to solve a computer issue. Peter is talking about the need to publish every result, positive or negative.
Specifically, the HP184 Phase IIb Proof of concept study was not published because it did not meet the primary goal of improving the ASIA score.
(So, in the light of what Dr. McKay said, should we understand that perhaps if there had been a better, more precise, scale of measurement the outcome might have been positive?)
Another example . . . the ProChord Trial was stopped in Phase II abruptly (over the weekend!) in 2006 because PreNeuron was depending on money from Big Pharma -- Big Pharma pulled the plug quite suddenly and that was the end of that. Mid-study, and nobody knows exactly what they were finding out. Seems like that would be good information to have, eh?
Talking now about a couple of orphan products -- not enough market to keep these companies viable. The free market system adds a level of complexity. Could other companies be at risk? The one that makes the Lokomat, for example?
What are we supposed to do about this? How do we deal with complexity?
1. continue basic research
2. publish ALL results, even the negative ones
3. concinue to reevaluate outcome measures
4. create new outcome measures
5. expand the market; look at collateral disease states
6. continue funding from the government, foundations and industry
7. stick to good science
8. do multicenter collaboration
9. get on a regulatory fasttrack
10 focus on realistic hope
donna is introducing panel that will include a man from Acorda, who I hope will explain where time-release 4AP is!
Specifically, the HP184 Phase IIb Proof of concept study was not published because it did not meet the primary goal of improving the ASIA score.
(So, in the light of what Dr. McKay said, should we understand that perhaps if there had been a better, more precise, scale of measurement the outcome might have been positive?)
Another example . . . the ProChord Trial was stopped in Phase II abruptly (over the weekend!) in 2006 because PreNeuron was depending on money from Big Pharma -- Big Pharma pulled the plug quite suddenly and that was the end of that. Mid-study, and nobody knows exactly what they were finding out. Seems like that would be good information to have, eh?
Talking now about a couple of orphan products -- not enough market to keep these companies viable. The free market system adds a level of complexity. Could other companies be at risk? The one that makes the Lokomat, for example?
What are we supposed to do about this? How do we deal with complexity?
1. continue basic research
2. publish ALL results, even the negative ones
3. concinue to reevaluate outcome measures
4. create new outcome measures
5. expand the market; look at collateral disease states
6. continue funding from the government, foundations and industry
7. stick to good science
8. do multicenter collaboration
9. get on a regulatory fasttrack
10 focus on realistic hope
donna is introducing panel that will include a man from Acorda, who I hope will explain where time-release 4AP is!
Dr. Naomi Kleitman from the NIH
Title of her talk is Getting On With Clinical Trials
What's the process? She's trained in basic science . .. we heard this morning that there are lots of potential targets. Slide is showing all the good targets, including neuroprogection, replacement of lost cells, repair of axons to promote regeneration and remove inhibition, remyelination, and retrain remaining circuits through rehab.
So many good targets!
And it's not care vs. cure anymore . . .they have to go together because rehab will be part of whatever works.
So, is walking the realistic target? Go look at clinicaltrials.gov -- of the 238 trials listed in sci at that website, what are they addressing?
sensory, bladder and bowel, sexual function, spastiticy, brething, pain, pressure ulcers, cardiovascular conditions. Her point is that we're somewhere along the path -- we're not het able to translate.
Ack! Image of a rat spinal cord and a human one, both kind of hemp-colored; against a purple background (image came fromDr. Bruce Dobkin, going to try to find it so you can see.)
The point is that what workds in the skinny little rat cord might be worthless in the human cord. Issues include the length of the cord, the size of the lesion, anatomy of each, and functional things, like walking on 2 leg vs. on 4.
Some fundamental questions -- neurological disorders are complex, and we need complex strategies to deal with them. The thing that researchers have to confront is, how much information is enough???
And there is disagreement about that among scientists themselves. There's no gold standard for cellular therapies and very little consensus about what that would be. How much recovery in animals justifies tests in humans?
Okay, so what is translation? It's changing one thing to another (thought to action) or carrying something from one place to another (bench to bedside)
It's not about doing a trial that isn't anything like what happened in the lab, and not using a therapy without some kind of rigorous assessment of what you knew.
What are the targets again?
neuroprotective strategies, neurorepair strategies (anti-nogo, NgR, cethrin, rolipram) -- you have to know what the outcomes mean.
The basic flow from thought to trial is:
ID the target, do an assay, do screening, establish proof of concept with animal models, do preclinical testing, do safety studies, take it to the clinic
she's talking about the difference between clinical reearch and clinical trials. Clinical research is basic science done with humans or human tissues, like epidemiology, physiology, pathology. Clinical trials test treatments in people for safety, efficacy and compared to other treatments.
What the FDA does is define three phases in the testing process. 1 is for safety, 2 is for safety and bioactivity, and 3 is for efficacy.
There was a spinal cord injury locomotor trial done recently on people with relatively new injuries. The trial "failed" because everybody walked and everybody in the control group walked, too!
Joking about how dumb some trials are with a phony randomized trial to see if it's dangerous to jump out of a plane with no parachute.
When will clinical trials begin?
They already have. There are currently 118 sci trials recruiting at clinicaltrials.gov
She says she can't talk about anything she knows about pending grants -- and asks us not to believe rumors that nothing is ever going to be tested.
There's a lot going on right now in sci -- more than in brain or stroke. the key is to figure out how to measure outcomes.
ICCP, ASIA/ISCoS, SCOPE, SCIQOL, EM-SCI, China SCINet, CDRF NOA, NETT . . . these alphabet soup nuggets are about planning collaborations. When I have some time I'll go find em and put the hyperlinks in.
Don't be fooled by clinical trials with bad designs. The problem is that when a design is bad you won't be able to tell if the drug failed or the trial failed. What you want from trials is reliable information.
She's talking about the icord document that tells people how to know whether or not they should think about enrolling.
Why does the FDA delay Phase I trials? Safety, safety, safety.
Getting to translation is hard. But we know much more than we ever have before, and my grad school advisor was wrong when he said that "spinal cord is boring."
What's the process? She's trained in basic science . .. we heard this morning that there are lots of potential targets. Slide is showing all the good targets, including neuroprogection, replacement of lost cells, repair of axons to promote regeneration and remove inhibition, remyelination, and retrain remaining circuits through rehab.
So many good targets!
And it's not care vs. cure anymore . . .they have to go together because rehab will be part of whatever works.
So, is walking the realistic target? Go look at clinicaltrials.gov -- of the 238 trials listed in sci at that website, what are they addressing?
sensory, bladder and bowel, sexual function, spastiticy, brething, pain, pressure ulcers, cardiovascular conditions. Her point is that we're somewhere along the path -- we're not het able to translate.
Ack! Image of a rat spinal cord and a human one, both kind of hemp-colored; against a purple background (image came fromDr. Bruce Dobkin, going to try to find it so you can see.)
The point is that what workds in the skinny little rat cord might be worthless in the human cord. Issues include the length of the cord, the size of the lesion, anatomy of each, and functional things, like walking on 2 leg vs. on 4.
Some fundamental questions -- neurological disorders are complex, and we need complex strategies to deal with them. The thing that researchers have to confront is, how much information is enough???
And there is disagreement about that among scientists themselves. There's no gold standard for cellular therapies and very little consensus about what that would be. How much recovery in animals justifies tests in humans?
Okay, so what is translation? It's changing one thing to another (thought to action) or carrying something from one place to another (bench to bedside)
It's not about doing a trial that isn't anything like what happened in the lab, and not using a therapy without some kind of rigorous assessment of what you knew.
What are the targets again?
neuroprotective strategies, neurorepair strategies (anti-nogo, NgR, cethrin, rolipram) -- you have to know what the outcomes mean.
The basic flow from thought to trial is:
ID the target, do an assay, do screening, establish proof of concept with animal models, do preclinical testing, do safety studies, take it to the clinic
she's talking about the difference between clinical reearch and clinical trials. Clinical research is basic science done with humans or human tissues, like epidemiology, physiology, pathology. Clinical trials test treatments in people for safety, efficacy and compared to other treatments.
What the FDA does is define three phases in the testing process. 1 is for safety, 2 is for safety and bioactivity, and 3 is for efficacy.
There was a spinal cord injury locomotor trial done recently on people with relatively new injuries. The trial "failed" because everybody walked and everybody in the control group walked, too!
Joking about how dumb some trials are with a phony randomized trial to see if it's dangerous to jump out of a plane with no parachute.
When will clinical trials begin?
They already have. There are currently 118 sci trials recruiting at clinicaltrials.gov
She says she can't talk about anything she knows about pending grants -- and asks us not to believe rumors that nothing is ever going to be tested.
There's a lot going on right now in sci -- more than in brain or stroke. the key is to figure out how to measure outcomes.
ICCP, ASIA/ISCoS, SCOPE, SCIQOL, EM-SCI, China SCINet, CDRF NOA, NETT . . . these alphabet soup nuggets are about planning collaborations. When I have some time I'll go find em and put the hyperlinks in.
Don't be fooled by clinical trials with bad designs. The problem is that when a design is bad you won't be able to tell if the drug failed or the trial failed. What you want from trials is reliable information.
She's talking about the icord document that tells people how to know whether or not they should think about enrolling.
Why does the FDA delay Phase I trials? Safety, safety, safety.
Getting to translation is hard. But we know much more than we ever have before, and my grad school advisor was wrong when he said that "spinal cord is boring."
Peter Wilderotter and Susan Howley from CDRPF
Peter says the big new thing is the establishment of CR foundation satellites around the USA. It will start in here in Chicago.
Our knowledge manager Sam Maddox is even wearing a suit, so we know that this must be an important occasion. He's acknowledging lots of local people here in the room who are already part of the program . . . also recognizing Marilyn, Sue, and Betheny. (Hey, Peter, you must get to know Donna!)
The path that got us here is not going to get us were we need to go . .. there's a quote up on the screen: "For everyone who thought I couldn't do it, for everyone who thought I shouldn't do it,for everyone who said I didn't ahve it in me, see you at the finish line!"
Dana said that having sci enter your family was landing on the moon without a map.
Mike Mangianella was in charge of sorting the mail, and there were 3 bins. The normal people, the people who might be crazy, and the people who were definitely crazy. (Not exaggerating here. People sent him kryptonite so he could be healed.) One of the middle bins got the letter from Joan Irvine Smith offering to send a million dollars because she was so pleased that he didn't shoot the horse that threw him. Her money started what became the RIRC.
Slide up about the history:
1982 was the beginning. Scientific dogma was that the cord could not be repaired. Patients were seen as a tiny isolated who had to stay on the sidelines. There was no awareness, and no collaboration.
Their thought at CDRF was that we can't get to the finish line on the same path that got us here. The path to the future has to be strategic.
Who is our community? 1,275,00 Americans living SCI, plus the newly injured, the families, caregivers, and friends, the health care providers, the scientists, and society at large.
He's introducing Susan Howley. The head of the ACLU is not a lawyer. How can that be? The constitution is too important to be left to the lawyers. And sometimes the science is too important to be left to the scientists. Susan has become the person in charge of not leaving it to the scientists.
She gets up to thank Peter and says that she just left the most gorgeous beach with the best weather ( a joke about the rain we have here) to be with us. She started working in this field in 1983 for a small family research foundation that started in New Jersey.
They gave $25,000 each to a couple of Columbia scientists who were into brain research.
So, while we're still an infant field, we've come an extraordinary distance in the last 26 years.
She wants to tell us how the Reeve foundation funds scientists; she's a herder of cats.
There are a couple of board members who have got their fingerprints all over the systems we have in place. It's a stepwise, dynamic continuum.
First is individual grants, which go to new knowledge and new talents. They funded Stephen Davies' original work on astrocytes, for example.
Next is an international research consortium, which is a multi-disciplinary collaborative approach to SCI repair.
Next is the NeruoRecovery Network, which delivers activity-based rehabilitation interventions to SCI patients
Finally, the North American Clinical Trials Network.
How do individual grants work? the mission is to cast a wide net and fund the development of treatments for paralysis and the other dysfunctions that result from sci
since 1982: a total of 610 labs funded worldwide with $47 million
since 2002: 202 projects with $25,000,000
They look for quantifiable ROI, including publications, subsequent funding, trainees, patents
Their grants cover the whole spectrum. neuroprotection, regeneration, growth inhibition, remyelination, axon guidance, rehabilitation, dysfunctions like bowel, bladder, pain and so on.
They hold a spinal cord symposium to promote dialgue between Reeve'sindividual grantees and members of the sci community, foster exchanges of data and ideas between the two groups, and facilitate collaborations among the researchres.
They also give small network collaboration grants, which are highly leveraged funding that supports collaboration.
The member labs of the consortium include the Miami Project, UCLA, Cambridge, The Salk Institute, State U of New York at Stony Brook, University of Zurich -- the core labs are The Salk Institute and UC Irvine.
In the Neuro REcovery Network, they create standardized, evidence based, activity based therapies. There are centers in Louisville KY, Philadelphia, Houston, Atlanta, Columbus, OH, Boston, and WEst Orange, NJ. They're also adding what they call Facilities (as opposed to centers), and one of them is even west of the Mississippi!
The clinical trials network is about getting to the bedside. This morning someone asked why there aren't more clinical trials . . . she says there have been trials, but they haven't worked. One problem with these earlier trials was that we had very clunky outcome measures -- they may have been effective therapies, but the outcomes were not measured very well.
The centers are in Texas (4), Virginia, Maryland, Ontario, Kentucky, Florida, Pennsylvania, Washington DC
Showing a complicated bar graph that measures number of research projects against project start date, with each bar broken into 9 possible segments. What jumps out is a huge drop in projects funded in the year 2006, along with the disturbing size of the segments that indicate "complications" in projects. (I'd love to see the data behind this graph.)
Peter is back . . . so, how do we get to the future?
1. The power of one (alliance-building, collaborations, elimination of duplicative efforts)
2. The power of the truth (striaght talk, expectation setting, replacing hype with hope)
3. The eternal mystery of the world is its comprehensibility (Albert Einstein) We need rigorous science and clinical trialing, along with a multi-faceted approach to repair. There's no magic bullet, no magical scientist or doctor, and no quick fix. We need strategic, science-driven decision-making.
He's quoting Ted Kennedy: The dream still lives . . .
He says that Sue and Marilyn and Betheny told him about going to meetings with people who were in the community but not interested in the word "cure" -- gives the example of early 1900's cancer situation. People used to be ashamed to use the word.
Wrapping is up, time for lunch.
Our knowledge manager Sam Maddox is even wearing a suit, so we know that this must be an important occasion. He's acknowledging lots of local people here in the room who are already part of the program . . . also recognizing Marilyn, Sue, and Betheny. (Hey, Peter, you must get to know Donna!)
The path that got us here is not going to get us were we need to go . .. there's a quote up on the screen: "For everyone who thought I couldn't do it, for everyone who thought I shouldn't do it,for everyone who said I didn't ahve it in me, see you at the finish line!"
Dana said that having sci enter your family was landing on the moon without a map.
Mike Mangianella was in charge of sorting the mail, and there were 3 bins. The normal people, the people who might be crazy, and the people who were definitely crazy. (Not exaggerating here. People sent him kryptonite so he could be healed.) One of the middle bins got the letter from Joan Irvine Smith offering to send a million dollars because she was so pleased that he didn't shoot the horse that threw him. Her money started what became the RIRC.
Slide up about the history:
1982 was the beginning. Scientific dogma was that the cord could not be repaired. Patients were seen as a tiny isolated who had to stay on the sidelines. There was no awareness, and no collaboration.
Their thought at CDRF was that we can't get to the finish line on the same path that got us here. The path to the future has to be strategic.
Who is our community? 1,275,00 Americans living SCI, plus the newly injured, the families, caregivers, and friends, the health care providers, the scientists, and society at large.
He's introducing Susan Howley. The head of the ACLU is not a lawyer. How can that be? The constitution is too important to be left to the lawyers. And sometimes the science is too important to be left to the scientists. Susan has become the person in charge of not leaving it to the scientists.
She gets up to thank Peter and says that she just left the most gorgeous beach with the best weather ( a joke about the rain we have here) to be with us. She started working in this field in 1983 for a small family research foundation that started in New Jersey.
They gave $25,000 each to a couple of Columbia scientists who were into brain research.
So, while we're still an infant field, we've come an extraordinary distance in the last 26 years.
She wants to tell us how the Reeve foundation funds scientists; she's a herder of cats.
There are a couple of board members who have got their fingerprints all over the systems we have in place. It's a stepwise, dynamic continuum.
First is individual grants, which go to new knowledge and new talents. They funded Stephen Davies' original work on astrocytes, for example.
Next is an international research consortium, which is a multi-disciplinary collaborative approach to SCI repair.
Next is the NeruoRecovery Network, which delivers activity-based rehabilitation interventions to SCI patients
Finally, the North American Clinical Trials Network.
How do individual grants work? the mission is to cast a wide net and fund the development of treatments for paralysis and the other dysfunctions that result from sci
since 1982: a total of 610 labs funded worldwide with $47 million
since 2002: 202 projects with $25,000,000
They look for quantifiable ROI, including publications, subsequent funding, trainees, patents
Their grants cover the whole spectrum. neuroprotection, regeneration, growth inhibition, remyelination, axon guidance, rehabilitation, dysfunctions like bowel, bladder, pain and so on.
They hold a spinal cord symposium to promote dialgue between Reeve'sindividual grantees and members of the sci community, foster exchanges of data and ideas between the two groups, and facilitate collaborations among the researchres.
They also give small network collaboration grants, which are highly leveraged funding that supports collaboration.
The member labs of the consortium include the Miami Project, UCLA, Cambridge, The Salk Institute, State U of New York at Stony Brook, University of Zurich -- the core labs are The Salk Institute and UC Irvine.
In the Neuro REcovery Network, they create standardized, evidence based, activity based therapies. There are centers in Louisville KY, Philadelphia, Houston, Atlanta, Columbus, OH, Boston, and WEst Orange, NJ. They're also adding what they call Facilities (as opposed to centers), and one of them is even west of the Mississippi!
The clinical trials network is about getting to the bedside. This morning someone asked why there aren't more clinical trials . . . she says there have been trials, but they haven't worked. One problem with these earlier trials was that we had very clunky outcome measures -- they may have been effective therapies, but the outcomes were not measured very well.
The centers are in Texas (4), Virginia, Maryland, Ontario, Kentucky, Florida, Pennsylvania, Washington DC
Showing a complicated bar graph that measures number of research projects against project start date, with each bar broken into 9 possible segments. What jumps out is a huge drop in projects funded in the year 2006, along with the disturbing size of the segments that indicate "complications" in projects. (I'd love to see the data behind this graph.)
Peter is back . . . so, how do we get to the future?
1. The power of one (alliance-building, collaborations, elimination of duplicative efforts)
2. The power of the truth (striaght talk, expectation setting, replacing hype with hope)
3. The eternal mystery of the world is its comprehensibility (Albert Einstein) We need rigorous science and clinical trialing, along with a multi-faceted approach to repair. There's no magic bullet, no magical scientist or doctor, and no quick fix. We need strategic, science-driven decision-making.
He's quoting Ted Kennedy: The dream still lives . . .
He says that Sue and Marilyn and Betheny told him about going to meetings with people who were in the community but not interested in the word "cure" -- gives the example of early 1900's cancer situation. People used to be ashamed to use the word.
Wrapping is up, time for lunch.
Doug and Stephen in a panel discussion
Rachel Hammerman is saying that a hallmark of this event is the ability of the audience to ask questions.
Woman asks if new scarring is a problem in other kinds of stem cell transplantations, like umbilical cells . . . he says he doesn't know, that maybe Wise will address that.
Wise gets up and takes the microphone to say that umbilical cells have not
scarred . . . he says that he and Stephen have a difference over the use of the word "scar" to talk about something that is not fibroblasts. . . (he can comment here later if I have that wrong.)
What I take from this is that there's some quite intense scientific disagreement.
Ahem.
Question about decorin . . what is it? what's it used for?
Stephen says that it's been around for a long time, but it hasn't been a stable molecule. There have been about 150 papers published about it this year. (Okay, I'll look these up later and read them.) We do know that it's well tolerated by the body and seems to somehow almost fool the body into thinking that the injury is smaller than it is. It's made by Integra Life Sciences and their partners.
. . .
For Doug: couldn't hear her. Doug is saying that SMA is a disease in which babies are born without any connection between the spinal cord and the neurons. The adult counterpart of that is polio or west nile virus. The first approach is going to be SMA, followed by west nile virus.
For Doug: Is there an animal model of transverse myelitis? Yes, and we've done that. We've made an animal model that very closely replicates the disease. The efficacy studies show modest gains, and the more we study them, the more learn about why it's not the "home run" we were hoping for. We're going forward.
Timeframe? Depends on funding for the company (California Stem Cell). The big pharmas are not yet interested in these biotech startups. Preclinical and toxicology studies are not done. We have to do the mundane, boring, oh-so-critical work. We're talking about $3 million . . . he asks Wise to comment.
Wise says $3 to $6 million. He's currently doing it in 2 countries for under $6 million.
Missed another question . . Stephen is talking about diffuse scarring and staining for protoglycans.
Question about scar tissue and untethering . . . Doug is saying that the gliotic area is inhibitory towards differentiation. (My thought -- Wise has some ground to stand on when he says that it's not helpful to use the word "scar" because it makes people visualize the thing that forms on the skin after a cut. It's not that.) Doug still talking about how we can use sophisticated neurobiology to alter the molecular environment in ways that Stephen's lab and others have shown is necessary.
Same woman, asking about muscle memory and using the FES bike. She's been using it for 2.5 years, and is at 49% stim for a ten mile ride. Doug says, "It's really cool that you got from being a passive participant to being a more than half do-it-yourself."
Says that we've known for a long time (40 years) that as you use muscles, your motor neurons adapt. What we don't know is why? That's what we're looking at now.
Question: I was at the last neuroscience meeting and understood about half of what was said . . what I want to know is, what's the hold up on clinical trials?
They don't take it, because Naomi Kleitman gets up to say she's going to address that right after lunch . . .
Bruce asks about induced pluripotent cells -- tell us what that is.
Doug explains that you can take a skin cell of your own forearm and dial it back to become an embryonic stem cell with your own DNA. He says that the danger we're in right now is that we could make the perfect the enemy of the good . .. we have lots of cells to work with, and this one is 10 years away from clinical applications. That skin cell has had a long life already, and asking it to go back to the beginning and become a stem cell is . . . well, a little scary.
Stephen says that it's a fantastic technology. But the real trick is not just in making them, but in controlling what they turn into.
Woman asks if new scarring is a problem in other kinds of stem cell transplantations, like umbilical cells . . . he says he doesn't know, that maybe Wise will address that.
Wise gets up and takes the microphone to say that umbilical cells have not
scarred . . . he says that he and Stephen have a difference over the use of the word "scar" to talk about something that is not fibroblasts. . . (he can comment here later if I have that wrong.)
What I take from this is that there's some quite intense scientific disagreement.
Ahem.
Question about decorin . . what is it? what's it used for?
Stephen says that it's been around for a long time, but it hasn't been a stable molecule. There have been about 150 papers published about it this year. (Okay, I'll look these up later and read them.) We do know that it's well tolerated by the body and seems to somehow almost fool the body into thinking that the injury is smaller than it is. It's made by Integra Life Sciences and their partners.
. . .
For Doug: couldn't hear her. Doug is saying that SMA is a disease in which babies are born without any connection between the spinal cord and the neurons. The adult counterpart of that is polio or west nile virus. The first approach is going to be SMA, followed by west nile virus.
For Doug: Is there an animal model of transverse myelitis? Yes, and we've done that. We've made an animal model that very closely replicates the disease. The efficacy studies show modest gains, and the more we study them, the more learn about why it's not the "home run" we were hoping for. We're going forward.
Timeframe? Depends on funding for the company (California Stem Cell). The big pharmas are not yet interested in these biotech startups. Preclinical and toxicology studies are not done. We have to do the mundane, boring, oh-so-critical work. We're talking about $3 million . . . he asks Wise to comment.
Wise says $3 to $6 million. He's currently doing it in 2 countries for under $6 million.
Missed another question . . Stephen is talking about diffuse scarring and staining for protoglycans.
Question about scar tissue and untethering . . . Doug is saying that the gliotic area is inhibitory towards differentiation. (My thought -- Wise has some ground to stand on when he says that it's not helpful to use the word "scar" because it makes people visualize the thing that forms on the skin after a cut. It's not that.) Doug still talking about how we can use sophisticated neurobiology to alter the molecular environment in ways that Stephen's lab and others have shown is necessary.
Same woman, asking about muscle memory and using the FES bike. She's been using it for 2.5 years, and is at 49% stim for a ten mile ride. Doug says, "It's really cool that you got from being a passive participant to being a more than half do-it-yourself."
Says that we've known for a long time (40 years) that as you use muscles, your motor neurons adapt. What we don't know is why? That's what we're looking at now.
Question: I was at the last neuroscience meeting and understood about half of what was said . . what I want to know is, what's the hold up on clinical trials?
They don't take it, because Naomi Kleitman gets up to say she's going to address that right after lunch . . .
Bruce asks about induced pluripotent cells -- tell us what that is.
Doug explains that you can take a skin cell of your own forearm and dial it back to become an embryonic stem cell with your own DNA. He says that the danger we're in right now is that we could make the perfect the enemy of the good . .. we have lots of cells to work with, and this one is 10 years away from clinical applications. That skin cell has had a long life already, and asking it to go back to the beginning and become a stem cell is . . . well, a little scary.
Stephen says that it's a fantastic technology. But the real trick is not just in making them, but in controlling what they turn into.
Doug Kerr, cont. and introducing Stephen Davies
Discussing a neurobiological change that happened with a group of secondary progressive multiple sclerosis, in which people who did FES bikes had changed
Sue is telling us that for 9 years since her injury she hadn't needed to use deodorant, but that since using her FES bike for the last several months, suddenly she needs it again.
(Wise is at the next table laughing . . . )
Sue is talking about Stephen Davies, whose title slide is up.
His researchers supported by David Van Wagener, the Lone Star Paralysis Foundation, the NINDS, CDRPF, NY state dept of health . . .
His beautiful astrocyte image is up while he give the agenda for this talk.
sci anatomy and basic concepts, factors preventing nerve fiber regeneration, the right astricytes, making gains and avoiding pains, and finally, what about chronics.
very high quality images, and great, simple to understand. He's saying that most axons descend and ascen the spinal cord in the white matter. you can get a spinal cord injury in the gray matter at the center of the cord and not lose function, but an injury that goes to the white matter destroys function.
the axons that are running up and down through the white matter actually send out little sidebars, into the gray matter, which is where the neurons actually sit. and we know that there are axons further out in the whte matter, not injured, that can send new connections into the gray matter . . . this is plasticity.
okay.
so, in a forming human being (in utero), an axon can regenerate itself, but after birth that's no longer possible.
why?
some theories:
old neurons just lose their ability
they lack growth support
myelin itself is inhibitory to growth
scar tissue is a physical and molecular barrier
slide shows and experimental spinal cord injury model
they made a lesion at c1/c2 in an adult rat and transplant adult sensory neurons, very very gently. they did fine -- but not when myelin was present.
talking about scar tissue as a barrier to axon regeneration
there's trauma and inflammation, severing of axons, loss of support cells, formation of inhibitory scar tissue.
What is those bloody freaking scars? (my words, not his)
CS Poteoglycans, liek kenurcan, brevican, NG2, . .. there are multiple inhibitory molecules . ..
what are come cell based sci therapies?
there are lots of non central nervous system cell types, like schwann cells, fibroblasts, olfactory ensheating cells, macrophages, embryonic and adult stem cells, marrow stromal cells, umbilical cord cells
and, there are cells of central nervous system origin . . . which ones are right? some astrocytes form scar tissue, and we think that 70% of all the cells in the cns are strocytes.
here's the progression . .. embronic stem cel to neuroepithelial stem cell to glial restricted precursor which can become either astrocytes or ologodendrocytes
but there are two kinds of astrocytes -- GDA bmp is the name of the one that works.
gotta say, it's very fun to listen to Stephen Davies talk. He has a very tony british accent, and way of communicating excitemnt and even wonder about his lab results. ("It's really quite amazing . . . "
Image up now that shows the GDA bmp got 60% of axons to grow across an injury site in 8 days -- the previous record was 5% after 3 months.
wow.
what happens if you but the undifferentiated stem cells into an injured cord? they turn into scar tissue.
people, this is why you don't want to take a chance on letting someone put stem cells into your cord.
they also tried the other kind of astrocytes, and the result of that was no sprouting across the injury.
what about functional recovery? they gave the rats c3/c4 injuries and make them walk across a little grid.
there were 3 sets of 9 animals -- some got no treatment, some got the wrong kind of astrocytes, and some got the bmp's -- the latter group were back to normal after 9 days.
oh, gak, he's saying that damaged neurons in the cord also means that there's damage to their former connections in the brain.
but, the good news is that bmp cells protect against that.
some potential benefits of transplangint the righ tastrocytes:
metabolic support for neurons, maitainence of of the blood spinal cord barrier, regulation of spinal blood flow, beidge of sci, regulation of oligodendrcyte development and prmotion of remyelination of axons, promotion of synapse formation and regulation of growth of dendritic spins, transmittion of calcium wave signals, reugulation of synapse activity
Stephen is the king of astrocytes.
And guess what? using the wrong kind of astrocytes leads to pain. The bmp astrocytes actually reduced pain, while the other kind raised it substantially.
Adult scar tissue astrocytes may be responsible for neuropathic pain.
Ah, on to decorin.
Decorin, Stephen has told us in the past, decreases the level of the proteins that suppress axon growth. it also breaks down scar tissue, which is great news for chronic.
talking about a rat 9 months after injury, showing a very depressing picture of damage far away from the injury site . . . so the question is, can decorin help?
adult neurons don't grow on myelin, and they don't grow on scar. but with decorin, wowza.
decorin boosts the ability of neurons to grow.
Stephen's agenda is still to get bmp and decorin together, and he's in the process of testing that combination.
"MY LAB IS NOW COMMITTED TO HEALING CHRONIC SCI."
Sue is telling us that for 9 years since her injury she hadn't needed to use deodorant, but that since using her FES bike for the last several months, suddenly she needs it again.
(Wise is at the next table laughing . . . )
Sue is talking about Stephen Davies, whose title slide is up.
His researchers supported by David Van Wagener, the Lone Star Paralysis Foundation, the NINDS, CDRPF, NY state dept of health . . .
His beautiful astrocyte image is up while he give the agenda for this talk.
sci anatomy and basic concepts, factors preventing nerve fiber regeneration, the right astricytes, making gains and avoiding pains, and finally, what about chronics.
very high quality images, and great, simple to understand. He's saying that most axons descend and ascen the spinal cord in the white matter. you can get a spinal cord injury in the gray matter at the center of the cord and not lose function, but an injury that goes to the white matter destroys function.
the axons that are running up and down through the white matter actually send out little sidebars, into the gray matter, which is where the neurons actually sit. and we know that there are axons further out in the whte matter, not injured, that can send new connections into the gray matter . . . this is plasticity.
okay.
so, in a forming human being (in utero), an axon can regenerate itself, but after birth that's no longer possible.
why?
some theories:
old neurons just lose their ability
they lack growth support
myelin itself is inhibitory to growth
scar tissue is a physical and molecular barrier
slide shows and experimental spinal cord injury model
they made a lesion at c1/c2 in an adult rat and transplant adult sensory neurons, very very gently. they did fine -- but not when myelin was present.
talking about scar tissue as a barrier to axon regeneration
there's trauma and inflammation, severing of axons, loss of support cells, formation of inhibitory scar tissue.
What is those bloody freaking scars? (my words, not his)
CS Poteoglycans, liek kenurcan, brevican, NG2, . .. there are multiple inhibitory molecules . ..
what are come cell based sci therapies?
there are lots of non central nervous system cell types, like schwann cells, fibroblasts, olfactory ensheating cells, macrophages, embryonic and adult stem cells, marrow stromal cells, umbilical cord cells
and, there are cells of central nervous system origin . . . which ones are right? some astrocytes form scar tissue, and we think that 70% of all the cells in the cns are strocytes.
here's the progression . .. embronic stem cel to neuroepithelial stem cell to glial restricted precursor which can become either astrocytes or ologodendrocytes
but there are two kinds of astrocytes -- GDA bmp is the name of the one that works.
gotta say, it's very fun to listen to Stephen Davies talk. He has a very tony british accent, and way of communicating excitemnt and even wonder about his lab results. ("It's really quite amazing . . . "
Image up now that shows the GDA bmp got 60% of axons to grow across an injury site in 8 days -- the previous record was 5% after 3 months.
wow.
what happens if you but the undifferentiated stem cells into an injured cord? they turn into scar tissue.
people, this is why you don't want to take a chance on letting someone put stem cells into your cord.
they also tried the other kind of astrocytes, and the result of that was no sprouting across the injury.
what about functional recovery? they gave the rats c3/c4 injuries and make them walk across a little grid.
there were 3 sets of 9 animals -- some got no treatment, some got the wrong kind of astrocytes, and some got the bmp's -- the latter group were back to normal after 9 days.
oh, gak, he's saying that damaged neurons in the cord also means that there's damage to their former connections in the brain.
but, the good news is that bmp cells protect against that.
some potential benefits of transplangint the righ tastrocytes:
metabolic support for neurons, maitainence of of the blood spinal cord barrier, regulation of spinal blood flow, beidge of sci, regulation of oligodendrcyte development and prmotion of remyelination of axons, promotion of synapse formation and regulation of growth of dendritic spins, transmittion of calcium wave signals, reugulation of synapse activity
Stephen is the king of astrocytes.
And guess what? using the wrong kind of astrocytes leads to pain. The bmp astrocytes actually reduced pain, while the other kind raised it substantially.
Adult scar tissue astrocytes may be responsible for neuropathic pain.
Ah, on to decorin.
Decorin, Stephen has told us in the past, decreases the level of the proteins that suppress axon growth. it also breaks down scar tissue, which is great news for chronic.
talking about a rat 9 months after injury, showing a very depressing picture of damage far away from the injury site . . . so the question is, can decorin help?
adult neurons don't grow on myelin, and they don't grow on scar. but with decorin, wowza.
decorin boosts the ability of neurons to grow.
Stephen's agenda is still to get bmp and decorin together, and he's in the process of testing that combination.
"MY LAB IS NOW COMMITTED TO HEALING CHRONIC SCI."
Welcome to Chicago!
We've just had opening remarks by Marilyn Smith from u2fp and Ida Cahill from the Sam Schmidt Paralysis Foundation . . . I typed them up and then the blog I was trying to use ate them -- I'll put em in later.
Right now Susan Maus is speaking from her chair, giving props to Marilyn for being the rock star that she is, and recognizing the speakers and sponsors. She's going to move right along with the program.
First up will Dr. Doug Kerr, who has not spoken at w2w before. He's director of the transverse myelitis group at Johns Hopkins . . . investigates neural stem cells and -- yikes, she's reading from a little bio and it's VERY full of jargon.
Here's Doug . .. 40 ish guy with a low voice, leaning with both arms on the podium.
title of talk is emerging restorative approaches in neurologic disorders
my task is to describe some science to you in a way that is understandable to the educated advocate . . . you're going to see the data . . . i'm going to tell you 3 small stories.
stem cells for demyelinating disorders -- challenges are differentiation, delivery, and immune rejection. Opportunities are non-cell replacement trophic support and early clinical trials will be coming soon.
next story is stem cells for motor neuron disorders
next will be novel restorative approaches based on functional electrical stimulation
---
first slide is up image of glial restricted precursors, which is could for demyleinating disorders.
basically what you want is a cell that can become one of the cells needed to fix things in the brain.
steve goldman published data in 2004 that showed that glial restricted precursors that were derived from human stem cells produced healthy myelin in a mouse.
big bright images that show tight wraps of myelin wrapping around an axon -- very impressive demonstration . . .
in another study, steve goldman showed that by 9 months after transplantation, the glial cells had filled the territory. these transplants were given to this strain of mouse called shiverer, which normally dies after a very short time. they lived normal spans after the transplants.
so, how do you get gmp (good manufacturing practices) grade cells?
we're moving forward and trying to get to a clinical trial as fast as we can.
the problem is that most of the precursor cells don't become oligodendrocytes (myelinating cells) . . . but we figured out how to tell if they were . . . specifically we figured out a way to make them glow (the screen shows hot green on a mouse's head) if they were oligodendrocytes.
cool.
showing a hugely magnified section of a damaged mouse cord. shows the migration of human glial restricted precursors to fill up the whole damaged space.
more evidence (graph-form) to show that the cells did indeed fill up the injury site.
so, do the cells help the axons to conduct signals more efficiently? they measured N1 latency and showed that they do -- sometimes all the way to normal.
what was the functional return? the transplanted animals had more grip strength than the untransplanted animals.
here's the weird thing -- the cells went in, they occupied the injured region, but they did not generally turn into oligodendrocytes. so, why did they work? that's a question that we need to investigate a lot more.
you're going to see a lot of clinical trials coming very soon
we didn't do a particularly good job of differentiating these cells in this first go-round . . .
____
conclusion -- myelin precursors do sirvive and migrate, cell replacement and remyelination is HARD but not impossible
they're going to try to get a "hit" -- a very successful trial, which means one that will show functional return right off the bat. for this purpose, the best choice for a trial subject is tranverse myelitis, because it's a singal focal lesion, it has the right pathology of demyelination and axonal loss, it's an easy surgery with a small trget, and thre are surrogate makers (which I don't understand and will try to ask about)
we hope to get these studies off the ground in early 2011
image on the screen of a demyelinated multipel sclerosis cord. it's pocketed with holes. so the problem is how to deal with all those lesions? can't be sticking a needle into a cord or brain 40 times.
so they have developed a protein that makes cells traveling through the blood bind to the kind of receptors that will get them to into the nervous system.
this is very cool. no surgery!
what about the problem of immune rejection? do we really have to put every patient on cyclosporin? it's very dangerous to make people susceptible to infection . . .
our approach is to find a way to teach the immune system not to freak out over the foreign cells . . .
some options - block the microglial activation, which leaves the immune system intact.
or, do a single tolerizing approach (which he doesn't explain, but says that the idea came from the kidney transplant folks) -- this has been done successfully in that realm.
Ann Neurol 2006
Right now Susan Maus is speaking from her chair, giving props to Marilyn for being the rock star that she is, and recognizing the speakers and sponsors. She's going to move right along with the program.
First up will Dr. Doug Kerr, who has not spoken at w2w before. He's director of the transverse myelitis group at Johns Hopkins . . . investigates neural stem cells and -- yikes, she's reading from a little bio and it's VERY full of jargon.
Here's Doug . .. 40 ish guy with a low voice, leaning with both arms on the podium.
title of talk is emerging restorative approaches in neurologic disorders
my task is to describe some science to you in a way that is understandable to the educated advocate . . . you're going to see the data . . . i'm going to tell you 3 small stories.
stem cells for demyelinating disorders -- challenges are differentiation, delivery, and immune rejection. Opportunities are non-cell replacement trophic support and early clinical trials will be coming soon.
next story is stem cells for motor neuron disorders
next will be novel restorative approaches based on functional electrical stimulation
---
first slide is up image of glial restricted precursors, which is could for demyleinating disorders.
basically what you want is a cell that can become one of the cells needed to fix things in the brain.
steve goldman published data in 2004 that showed that glial restricted precursors that were derived from human stem cells produced healthy myelin in a mouse.
big bright images that show tight wraps of myelin wrapping around an axon -- very impressive demonstration . . .
in another study, steve goldman showed that by 9 months after transplantation, the glial cells had filled the territory. these transplants were given to this strain of mouse called shiverer, which normally dies after a very short time. they lived normal spans after the transplants.
so, how do you get gmp (good manufacturing practices) grade cells?
we're moving forward and trying to get to a clinical trial as fast as we can.
the problem is that most of the precursor cells don't become oligodendrocytes (myelinating cells) . . . but we figured out how to tell if they were . . . specifically we figured out a way to make them glow (the screen shows hot green on a mouse's head) if they were oligodendrocytes.
cool.
showing a hugely magnified section of a damaged mouse cord. shows the migration of human glial restricted precursors to fill up the whole damaged space.
more evidence (graph-form) to show that the cells did indeed fill up the injury site.
so, do the cells help the axons to conduct signals more efficiently? they measured N1 latency and showed that they do -- sometimes all the way to normal.
what was the functional return? the transplanted animals had more grip strength than the untransplanted animals.
here's the weird thing -- the cells went in, they occupied the injured region, but they did not generally turn into oligodendrocytes. so, why did they work? that's a question that we need to investigate a lot more.
you're going to see a lot of clinical trials coming very soon
we didn't do a particularly good job of differentiating these cells in this first go-round . . .
____
conclusion -- myelin precursors do sirvive and migrate, cell replacement and remyelination is HARD but not impossible
they're going to try to get a "hit" -- a very successful trial, which means one that will show functional return right off the bat. for this purpose, the best choice for a trial subject is tranverse myelitis, because it's a singal focal lesion, it has the right pathology of demyelination and axonal loss, it's an easy surgery with a small trget, and thre are surrogate makers (which I don't understand and will try to ask about)
we hope to get these studies off the ground in early 2011
image on the screen of a demyelinated multipel sclerosis cord. it's pocketed with holes. so the problem is how to deal with all those lesions? can't be sticking a needle into a cord or brain 40 times.
so they have developed a protein that makes cells traveling through the blood bind to the kind of receptors that will get them to into the nervous system.
this is very cool. no surgery!
what about the problem of immune rejection? do we really have to put every patient on cyclosporin? it's very dangerous to make people susceptible to infection . . .
our approach is to find a way to teach the immune system not to freak out over the foreign cells . . .
some options - block the microglial activation, which leaves the immune system intact.
or, do a single tolerizing approach (which he doesn't explain, but says that the idea came from the kidney transplant folks) -- this has been done successfully in that realm.
Ann Neurol 2006
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