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Thread: Live from Working 2 Walk 2011!

  1. #41
    Thanks Kate for keeping us informed. I've followed the progress/this site since my oldest was with a classmate who dove into a pool and sustained a C5 injury... jeepers... 7 years a go. You and everyone are doing a great job. I'm happy to write checks when I can. Your posts help me direct my small checks to the groups/projects that I think could restore function for him and all who have sustained injury. Again, many thanks. You rock.

  2. #42
    Interesting information and participations. I want to thank everybody again and Paolo too to gave voice to the thoughs of many sci people. I also agree with Scaper1 about bureaucracy..... another big problem.....

  3. #43
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    Quote Originally Posted by Schmeky View Post
    Kate,

    Thanks for all your hard work and effort. It is appreciated. What I have not really picked up on is any type of concrete time frame to take something to trial for chronics. But this doesn't surprise me.

    Perhaps this will surface during the seminar.
    Hi David, maybe Kates post #24 addresses some of this

    Great blogging Kate!

  4. #44
    Senior Member Schmeky's Avatar
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    Leif,

    Kate's post #17 is the one that caught my attention. I agree in part the problem is a component of engineering, combined with cell transplatation.

    These guys (Invivo) make more sense, and "seem" to have a much more real approach, than anything I have read.

    I have been looking for someone to support for real results and these guys look good, at least presently.

  5. #45
    Senior Member kate's Avatar
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    Anthony Caggiano: Chondroitinase Overview

    Good morning, sports fans ~

    Marilyn's about to go to the microphone for announcements, then we'll get to Anthony Caggiano, who's the VP of pre-clinical development at Acorda Therapeutics.

    Here she is: Today's gonna be another very busy day, so we need to get started on time and stay that way . . . yesterday was sort of a head-spinner. For those who might not feel like you remembered everything you heard, keep in mind there will be video up at u2fp just as soon as we can get it edited and online.

    Also, there's that blog thang.

    Raffling a video camera and an iTouch, get yer tickets! It's one of the ways we get cash to fund this conference and keep it affordable. There's a survey in your packet, which we always use to tweak this event, so please fill it out & be candid. This needs to be for you.

    Tonight there's a reception at Kennedy Kreiger, and we arranged transportation over there . . . still have a little room. Buses leave at 5:45, return at 9:15, dinner provided. About 70 of you are already signed up & we still have room.

    Donna's coming up to do the intro for Dr. Caggiano. He's here representing one of the few biotech companies working on chronic sci. Hundreds of studies have been published about chrondroitinase (hereafter called Chase).

    Caggiano:
    I'm the only person in the room with a tie on!

    For those not familiar with Acorda, we were founded with the mission to develop therapies for sci. We made dalfampridine and ran clinical trials for sci and made it into phase 2 with them, but didn't get the results we had hoped for. We also tried it with ms, and those trials did succeed.

    Right now there are 3 active development programs for sci, which I'll talk about a little, but I was asked specifically to talk about Chase. Most of what I'm going to do is talk about what other people are doing with this enzyme . . . that's because it's a big strength of this enzyme that everybody has done so much work with it. It's well understood.

    Historically, the work goes back 20 years; Chase is correlated with expression of inhibitory molecules on reactive astrocytes, and with functional improvements.

    Slide up about a paper Davies published back in 1999 about robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. Soon after that (2001) another paper in Nature Neuroscience, and a year later one in Nature by Liz Bradbury at Kings College showing that Chase ABC promotes functional recovery after sci. She had rats crossing ladders. The functional improvement was out of proportion to the regeneration, which seemed to mean that other things were happening -- that Chase was affecting some other factors that had been preventing recovery. At the same time, Pizzorusso published Reactivation of Ocular Dominance Plasticity in the Adult Visual Cortex . . . this paper was important because it showed that things could be improved long after injury.

    At Acorda, they showed that Chase could improve locomotion and bladder function after contusion injury in the rat spinal cord, published this in Journal of Neurotrauma in 2005.

    Skipping to 2011, one scientist has shown that Chase combined with rehab promotes recovery of forlimb function in rats with chronic sci. This was a c4 dorsal cut injury; at 1 month post, the rats got the drug.

    Chase delivered after a t10 hemisection in cats improved motor function. This paper was published in experimental neurology in 2008 by Nicole Tester an Dena Howland. However,rats are one level of difficulty and cats are orders of magnitude more complex.

    So they did work with cats, and got the same kind of promising results.

    What all this means is

    There's clear evidence that Chase alters capacity for regeneration and plasticity
    There's strong scientific rationale for Chase promotion of plasticity, sprouting and regeneration
    There's evidence that Chase promotes functional recovery in lots of injury models
    There's evidence that it works in multiple species: rats and cats
    There's evidence from multiple independent labs that it works

    So what's the hold up?

    Colleagues have reported numerous negative studies --
    Using Chase is a challenge, partly because delivery remains an issue --
    There is as yet no safety record.

    What has slowed the progress into human studies is . . .

    From Liz Bradbury's work: if you put Chase at c5 into a rat cord, the distribution into the cord isn't very impressive . . rat cords are 9 cm, which is less than a third of the human cord. The area of a section of rat cord is 12.5 square mm, compared to about 100 for humans. So if Chase only spreads for 3 to 5 mm, how do you get greater distribution in humans? How many segments would you need to get results?

    Slides showing visually the differences between the cross section of the human cord and the rat cord. Chase works when it gets to the gray matter in the center. It's a lot further to get there in humans than in rats.

    Acorda now has 3 active programs in sci, for acute, subacute, and chronic (the chronic one is Chase)

    Next steps: Find out if distribution (getting to the gray matter) is possible in pigs; this is being tried right now with a contract organization, using direct injections and intrathecal infusions.

    Explore feasibility of direct injection, is it safe, will surgeons do it . . .

    Find alternative means of delivery, using matrices or viral vectors; this is happening at Liz Bradbury's lab; it's working quite well but it's not clear how to "turn it off" . . .

    What other methods are there to manipulate these enzymes?

    They're looking a manipulating chase so that it stays stable at 37 centigrade, which is human body temperature.

    Yikes, that was fast for 8:30 am . . .

  6. #46
    Senior Member kate's Avatar
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    Dr. Jerry Silver Case Western University

    I'm privileged and honored to be able to talk to you about our work. I'm going to give you 2 slides that cover 30 years of work showing why regeneration is so hard, then some good news:

    Cajal put a knife into the back of a cat . . . axons retreat from the injury. He thought that the axons dried up and disappeared, but we know now that they just stay there indefinitely, waiting to be reawakened. Just a few can sprout, just a few and very slowly.

    There are molecules called proteoglycans that play a major in regeneration failure. In embroys there are places where axons don't grow normally, and it took decades to understand that those proteoglycans are involved in those places. In particular, there's one called NG2. They're thought to be a kind of glue, preventing the loss of what's been "learned" but also, unfortunately, acting as scars.

    What happens after injury, you have an inflammatory event in the center of the lesion, and macrophages show up, acting like little pacmen, driving the nerve fibers back. There are stem cells inside your cord, but they're trapped around the outside of the lesion. What Chase does is allow the nerve fibers to move within the lesion, but then when they get to the scar they're stuck.

    We decided to bypass the whole damn thing with a peripheral nerve graft.

    You can graft nerves and get them to go into the injury but you can't get them to come out

    So they looked at peripheral nerve bridging and adding Chase; in 2006 they fixed the extensor muscle in a hemisected cat's paw . . . okay, so if we can fix one muscle, can we fix another?

    Okay -- WATCH THIS VIDEO WHEN IT GETS POSTED. IT'S NOT POSSIBLE TO DO JUSTICE TO WHAT HE'S SAYING WITHOUT ACCESS TO THE IMAGES THAT HE'S REFERRING TO.

    When you make a lesion, nature creates what amounts to a giant net all around the spot . . .our idea was to add some Chase and see if we could penetrate that net. We only got about 10%. So we did a bridge of peripheral nerves and added Chase both above and below the lesion.

    They were focused on just one muscle and one graft. This paper is published in Nature in 2011. They were trying to cross this giant chasm of less than 1/2 of a millimiter.

    The respiratory rhythm neurons was their target.

    Return of diaphragm function, albeit very slow, is always patterned, never chaotic except for occasional skipped breaths as well as variations in amplitude between individual breaths. True functional regenration takes time!

    The quote above is directly from the slide . . . they waited for 8 weeks and didn't see recovery of regular breathing, got depressed, thought they had failed, put the rats away for further consideration. A month later somebody noticed that something had changed with the rats' breathing. They just hadn't waited long enough -- which is probably why there's an exclamation point on that slide.

    Importantly: cutting the graft completely eliminates returned activity in the diaphragm, proving that regeneration through the graft is critical for functional recovery.

    What about bladder/urinary/(and bowel/sexual!)function? Can our strategies be used to allow paralyzed animals and hopefully humans to urinate normally after sci?

    They did a t8 transection in a rat. Did the peripheral nerve graft, added the Chase, and waited. And waited. And they saw neurons growing.

    He's playing the sound of normal peeing in a not-paralyzed rat, and then in an anesthetized rat . .. God, I love science.

    What about chronic injury? They went one full year with the respiratory model in a rat. A single injection in the vicinity of the phrenic motor pool one year after c2 hemisection led to significant activity. This is very, very good news.

    Aaahhhh. I can't wait for the breakout session with this guy. Watch the video, soon to be up @ u2fp.org

  7. #47
    Senior Member kate's Avatar
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    Dr. Keith Tansey, Director SCI Research and Restorative Neurology, Shepherd Center

    He has a PhD in spinal cord physiology, is board certified in neurology and sci medicine, serves on the board of directors for ASIA and the American Society for Neurorehabilitation, works at the SCI clinic at the Atlanta VA, the animal lab at Emory, and the human lab at the Shepherd Center

    Shepherd is the biggest neurorehab hospital in the us, member of SCI model systems and the neural recovery network, icu to outpatient rehab, and has a dedicated human researarch lab for sci called SCIL

    www.shepherd.org/research/spinal-cord-injury shows 38 projects enrolling patients and providing an online intake form for those who want to participate in research. Register into their database!

    Showing cross sections of two injured cords, one with a bunch of holes in it, like swiss cheese, and one with a dark lesion in the center. The swiss cheese one was a walker, the other completely paralyzed. Why?

    What's known is that you have sensory and motor neurons going to and from the brain; in completes, the circuitry fails completely. In incompletes, some remains. About half of "clinically complete" injuries have existing circuitry.

    So what is the neural circuitry for locomotor recovery after sci and how might we enhance that recovery? There is plasticity in sensory neurons that's sufficient for training stepping in animals with complete spinal cord transections.

    About to show a guy walking with a walker, a gait belt, and a trainer. He's had 2 weeks of lokomat training. It looks very hard. So they put him back into the lokomat . . . video shows him in the machine, looking very cmfortable. 12 weeks later, he's walking fairly normally with one laufband crutch.

    Who benefits from this kind of training? It depends on a lot of variables. Do you have voluntary bowel and bladder? Do you have spasticity? Do you walk at all? How long since your injury? Using these variables, they can do the math and predict how much walking speed will improve. Could they figure out how to get everybody to improve a lot, rather than just the people who met certain thresholds in those variables?

    So they did brain imaging to look at what was different in the brain between those who could improve and those who couldn't . . . then attached an electrode to the back of the reflex at the back of the knee of some subjects to look at (and stimulate) reflexes under various conditions, comparing uninjured, incompletes, and completes.

    What they saw was that it might be possible to sort of "work through" the hyper reflexes and calm them down over time. Re-training the existing nerves to do what they're meant to do.

    What they're doing now is stimulating posterior root muscle reflexes and classical soleus H-reflexes. . . . quads, hamstrings, triceps, and tibialis.

    Okay. The idea is to combine electronic stimulation with the sensory feedback that comes with lokomotor type exercise and see what happens.

    The lokomat becomes a scientific recording device that allows them to figure out how loading, gait speed and electric stimulation should best be combined. It lets them calibrate exactly how to, for example, fight tone so that walking becomes more normal. Showing that in a patient with bad clonus they can give the cord exactly how much stimulation it needs to one muscle group to overcome the one that is spazzing.

    We anticipate that an integrated use of transcutaneous spinal cord stimulation and locomotor training may promote faster or greater recover of locomotion . . .

    Break time.

  8. #48
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    Quote Originally Posted by Christopher Paddon View Post
    Do you do the treadmill training at home?
    We have opened up a small gym with equipment we purchased for my son. We needed more space than was available at home so bought a small building to use. We have a rti 300 arm and leg stim bike, a homemade treadmill using air operated linear actuators to adjust the amount of weight bearing, standing frame glider, parallel bars, a tracksystem built into the ceiling for overground training, mats, Empi units, and more. We purchased all of the equipment for my son because insurance wouldn't pay because he is complete. All told we have 100K in equipment cost. We have part time employees with 1 PT and 5 physiologists who are very flexible with their time between us and a local gym. We have 5 sci people using the gym for free(we owned the equipment already) we ask that if they can they can help pay the physiologists. If we went to full time we could operate the gym for about 250K/yr. That cost would cover 10 people getting 4 4 4 split between the treadmill and other over ground therapies.

    Using a medical model therapy we would have to provide mental services, physician services, all PTs(most won't last a day on the treadmill), nursing services and many other unnecessary services driving the cost up by as much as 1,000%.

  9. #49
    Senior Member kate's Avatar
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    Dr. John McDonald, Kennedy Krieger VP & Director

    The good news is that the nervous system is turning over all the time, cells are being born all the time. I started off at Washington University, where we were focused on acute injuries, but at KK we deal with people who live with paralysis. We have a sub-focus on pediatric sci and paralysis, and program designs for an individualized, lifelong, in home restoration therapy rehabilitation program.

    There's so much that's doable today, and everyone who needs it should have access to all of it.

    Agenda: The problem, Goals for restoration, Approaches to regeneration, Elictircal stimulation, Problem of reduction of activity, How activity is related to recovery of function, How to meet the cure halfway.

    Showing the mri of someone with a 20+ year injury. The cord dies from the inside out. At the center is the lesion and outside is "scar tissue" -- which used to be thought of as just dead stuff. Modern imaging shows that it's not. We've imaged a lot of cords of people who are Asia A, and the majority of them have plenty of surviving neurons.

    We want to reduce complications . . . 30% of sci require readmission to hospitals every year.

    John is showing his famous sketch from a 1999 Scientific American article; I'll try to find a copy to post in here.

    Regeneration strategy: optimize regeneration by normalizing levels of neural activity . . . using patterned neural activity that's fundamental to development and regeneration.

    Completely transect a rat at t8, implant a chip below the lesion, activate the peroneal nerve, expect to see enhanced indicies of regeneration . . . and we do.

    FES Locomotor Activity promotes progenitor cell generation (Li et al. Neurosci 2010)

    Okay . . . this means that electrical stim plus the right kind of activity is actually making new cells. And they can use markers to know if the cells are oligodendrocytes, astrocytes, neurons.

    Baclofen inhibits proliferation of cells . . . rats treated with baclofen get less functional recovery, too. We need to be careful about what drugs we're taking.

    Why use FES?
    -No pragmatic option for benefiting from physical activity with paralysis.
    -Benefits of moderate physical activity in paralysis are overwhelming and doable in the home.
    -Neural restoration is possible.
    -Regular, near normal input optimizes the nervous system for recovery.
    -Achieving significant, incremental improvements at any time following injury is possible.

    Showing video of an FES bike with a voiceover talking about the cellular benefits of FES biking. I guess I thought that everybody in this room and everybody reading this on CC has known this forever, but if not -- it's real. It's known.

    The issue we have is that there's a technological barrier to getting this into every single home where someone who needs it has access to it.

    Some clinical studies -- you can reverse physical deterioration, reduce complications, recover neurological function.

    Even very delayed recovery is possible: Chris Reeve.

    Went from Asia A to Asia C, 5 - 8 years recovery, 0 to 20% motor score recovery, went from 7 to 60% sensory recovery, had a 10-fold reduction in infections and use of antibiotics, improved his quality of life, enabling him to travel.

    Study Outcomes
    Most people lose function over a 3 year period
    RT subjects doubled muscle mass and halved fat mass and reduced spasticity
    RT subjects also reduced baclofen use for spasticity

    Asia conversion rates:
    A to BCD 33%
    B to CD 40%
    C to D 14%

    This is just the beginning of the curve; we're just learning how to manage all this, how to get this into peoples' homes.

  10. #50
    Senior Member kate's Avatar
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    Panel: Caggiano, Silver, Tansey, McDonald

    All the guys from this morning's presentations are taking questions from the audience . . .

    Q: Basically, can you please hurry up with this Chase project?
    A: We really are trying very hard . . .

    Q: What kind of resources are you committing in terms of actual dollars? We need to get this into people . . enough with the rats.
    A: The Chase project studies cost hundreds of thousands of dollars, and if they're successful we move on to the more expensive parts
    A: (Silver) When basic science shows the kind of very promising result I showed a little while ago -- one injection, one week later, one year after injury -- there should be word of mouth, there should be -- I don't think money is the problem. If we're good enough to pass the peer review system, we should be able to get grants, we should need only 10 to 50s of thousands of dollars. If you put 15 million dollars into my lab, we can't go faster, we can just do the same thing a ta bigger scale. I will put my own grant money into this project, I don't need any more resources. I do need support to take the work from my lab to the clinic.

    Q: What shape would that support take, getting from the lab to the clinic?
    A: (Silver) Tony gave you an array of papers that showed that Chase has an effect; there's plenty of evidence out there . . . how do we flip the switch to get this to clinical trials . . . I don't know if there's a bottom line, but acorda's got to help. They've made some nice pure enzyme, and they're going to be looked around the wolrd All of you can talk to your physicians, some hospital somewhere is likely to try. It's so close.

    Q: Dr. Tansey, how does your work translate into outpatient services once they leave.
    A: These things run largely in parallel. Because we have ongoing research in so many areas, we have a high level of understanding of research by the clinical staff . . .the patients involved in care are able to enroll in studies. We have some patient populations seved better than others. An important part of translational research is the difficulty of getting from the lab to the human. It's great to see an example of something that works in an animal . . . how are they different? Then there's safety. Put me in a trial, I can't do any worse, yes you can, you can be in pain all day long for the rest of your life. Is there something between animal research and a clinical trial. Can we take 5 or 15 patients and see what kind of results you get. Do we really need millions of dollars to have multiple centers. Is there a rat equivalent for humans? The perception is that we aren't getting things to clinics with what we know . . . the reality is that the best thing you can do is work with a good therapist, take advantage of "practice-based evidence" -- the opposite of evidence-based practice.

    Q: I think it's ridiculous to suggest that funding is not a problem. If additional funding only allows you to test more rats, why not move to a chronic primate model and improve your end.
    A: Mark Tzyinsky is doing Chase with primates. Another 1/4 of a million per year in my lab
    Q: Why not go to a primate model first?
    A: They're very expensive ..
    Q: But doesn't that mean funding IS a problem?
    A: If there's a remarkable result, and people see it, and the NIH sees it, and grants are written, we shouldn't have to ask YOU. I think if the science is good, the money will come. We need to get our work peer-reviewed, we just have to earn it.
    Q: I have no doubt that everyone is here for the pure science . . . if you were only here to get rich, we'd all LOVE to see you get filthy rich . . .I think there's this "I'm not in this for the money" and I just want to say, I don't care if you are, as long as it goes faster.
    A: (McDonald) Another factor that it's a factor that a lot of young people are not coming into this field, because it's not that well-funded, and new ideas often come from new people. The shifting of NIH money toward this field has the effect of drawing talent.

    Q: Jack Kerouac's quote: those who are crazy enough to think they can change the world are generally the ones who do. About baclofen, how do you manage spasciticy if you don't take it?
    A: (McDonald) Baclofen often starts in the acute setting when spasticity is bad. But then the dosage gets raised and raised, and you have a new doctor who's not that versed in sci care, so you stay on it forever. And it's not really doing anything of value for you. We have other ways to deal with the issues it's supposed to deal with. The majority of people on baclofen are not getting the benefit they think they are, and it's very doable to get them off it. How do we optimize our patients.

    Q: In regards to FES for caudaequinal injuries . . . any new ideas? I did the FES bike for months and only got flickers.
    A: (McDonald)All CE injuries are not complete and nor are they all the same. There are things that can be done in order to move you forward, to get those muscles to contract --
    (Tansey) If you have nerve cells, you can use classic FES, if you don't, you can use another kind of stimulation -- and this is testable so we know which it is.

    Q: With regard to the locomotor plus stimulation training studies , what was the average duration of the studies?
    A: (Tansey) 3 times a week, 1 hour a day, for 3 months

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