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Thread: Live from Working 2 Walk 2010!

  1. #21
    Senior Member kate's Avatar
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    Afternoon sessions: Phil Horner

    Sue is introducing our buddy David Zach, father of three, u2fp board member, and c5-injured rock star advocate.

    David introduces Phil Horner, who's making his first appearance at w2w.

    Horner is youngish and wearing a dark suit with purple shirt . . . shows us a slide of the space needle (home!) now a pic of his daughter on her first day of first grade, beaming.

    He says he feels like her -- wild with excitement and also knowing that it's only first grade, the state of his lab.

    Outline:
    sc stem cells are active throughout life
    endogenous stem cells contribute to sc repair
    transplanted stem cells improve function following acute injury
    how do we recreate the post-injury period of repair in the chronic condition?

    Brain cells are replaced in select areas of the brain; but that declines a lot as you get older. This means that your own brain is plastic, in the sense that it's changeable and capable of growth.

    In the last 10 years, it's also been learned that spinal cord cells are replaced throughout life. Your cord does NOT create neurons, but it does create glia ("glue" cells) -- glia are involved in plasticity and in making connections. This is good news. As you get old, the pace at which glial cells replace themselves gets faster -- the opposite of what happens to neurons in the brain. We all lose myelin as we age, but our glial cells are replacing it.

    So, damn. Why don't these cells replace axons. There are some organizations that regenerate things super well. Pic of a starfish, which can regenerate a whole arm . . . also an arm can grow into a whole new body.

    Salamanders can regenerate limbs . . . you can take a limb bud and stick it on the salamander's head, and it will grow that limb out of the head.

    They also regenerate their spinal cords, right from the get go.

    What happens in mammals? Our injured cords generate glia almost exclusively . . . we don't make neurons. Some of the glia are helpful b/c they make myelin, some are life-sparing but they mess with return of function.

    Repair can be done. It's most likely an engineering problem at this point.


    Stem cells replace glia after sci . .. especially when injected early after injury. Chronic injuries don't benefit as much as we need them to.

    Sam Nutt is a researcher who's working on "the magic brew" induced pluripotent stem cells. (known as iPS cells). What they did was figure out which genes make an embryonic stem cell what it is. The genes are already there, but they're "turned off" -- if you could turn 'em back on, you could put them into an adult skin cell and reprogram it to turn it into an embryonic stem cell.

    Your adult skin cell can be turned into one of the stem cells that made you in the beginning. That stem cell can then be induced to become other kinds of cells, including cells from the nervous system. It takes 9 days to take cells that were skin cells and turn them into cells with properties of neurons.

    Sam . . . Sam could be our new best friend. Sam has been working on turning those iPS-created cells into the right kinds of neural glia. They have to look at thousands of genes and make sure they're switched on and off in exactly the right combination.

    Now have a phase 1 iilot study for preclinical trial with ips-derived glial precursors for chronic lesions of sci.

    (Preclinical means rats.)

    On the forelimb reaching task, you measure how well the rat can reach out and grab a pellet. They took human skin cells, turned them into glial cells, and put them into the rat. A month out from injury, they put the cells into the rat, it did have dramatic improvement, which disappeared with immune system protection withdrawn.

    They'll be producing patient specific cell lines under GMP conditions
    They'll find out if stem cells create a zone of plasticity
    They'll figure out how to collaborate with other scientists . . .

  2. #22
    Senior Member kate's Avatar
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    Stephen Davies, Local Hero

    Controlling scar formation and making the right kind of astrocytes.

    Spinal cord pathways . . . Stephen always has beautiful slides, but too full of information to do justice this quickly in words. Please check out the video of his talk when we get it up.

    He's saying that the contusion fills with astrocytes and macrophages.

    Sadly.

    What are the reasons we don't regenerate our damaged cords? Some theories:

    old neurons lose ability
    no growth support
    myelin is inhibitory to growth
    there's scar tissue, a physical and chemical barrier

    Stephen is interested in the scar tissue phenomenon. There are all these things growing into the injury that act as "scar" . . . basically he's saying that they found that some of the stem cells already in the cord are preventing regeneration . . .which is why you'd want to be very careful what kind of cells you put in there.

    It's one thing to get axons to cross the injury site, but another to get them to form collatorals . . . little side branches.

    They have 2 major repair strategies
    one is to overcome scar and myeling inhiotors to promote axon growth
    promote specific types of astrocytes

    Showing a list of all the cell based sci therapies, starting with the nonCNS ones, like schwann cells, olfactory ensheathing eclls, esc and asc

    he's looking instead at cns cells . . 70% of cns cells are some kind of astrocyte

    are they good candidates?

    Well . . . they provide metabolic support for neurons, they maintain the blood spinal cord barrier, they bridge the injury site, they promote remyelination of axons, they promote formation of neural connections and growth of dendrites, they transmit calcium wave signals through astrocyte networks, they regulate synapse activity with gliotransmitters (think that last word is a new term invented in his lab) -- in short, astrocytes are essential components of brain and spinal cord neural networks.

    So, can we make the right kind of astrocytes?

    the path is:
    esc becomes neuroepithelial stem cell, which becomes glial restricted precursors, which become a couple of kinds of astrocytes -- they've made what they call GDAsBMP, which are the good kind of astrocytes.

    Plan to collaborate with Phil Horner to get a source of them through iPS --

    They used their GDAsBMP cells created fast, reliable axon growth. The other kind of astrocytes stops growth cold, as did plain old stem cells.

    Did the axon growth contribute to functional recovery? Absolutely, and quickly.

    Okay, so we heard that he was going to talk about suppressing scar formation. That gets us decorin.

    Chronic . . . what can decorin do to promote axon regeneration in the chronically injured spinal cord?
    Can you increase enzymes that break down scar tissue?
    Can decorin desensitize

    if you add decorin to adult sensory neurons , you see axon growth. Decorin promotes growth AND attacks the growth inhibitors.

    ongoing studies: testing human decorin and gdasbmp in chronic sci contusion sci models
    combining same with rehab
    develop same for human clinical trials.

    Panel: Davies, Horner, Bruce Hanson, JenJen

    Question: Is it really hard to make an iPS cell out of a skin cell?
    Horner: No, that's simple enough for anyone to do with a kit. What's very hard is to turn them into what you want them to be. Another issue is that the FDA doesn't want us to use viral vectors to do the iPS switch, which means we have to come up with another way.
    Last edited by t8burst; 06-05-2011 at 12:50 PM. Reason: privacy

  3. #23
    Senior Member kate's Avatar
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    Panel.

    Question: What can we in this room do to help you guys?

    Davies: Funding. Bad economy, slow NIH = slower research.
    Horner: NIH is the elephant in the room, and the squeaky wheel gets the grease, so squeak. Squeak.

    Question: are iPS cells going to be able to help by going around the esc "ethical" argument? (quotes around ethical are mine -- sorry. I think the fact Geron has taken stem cells from a single blastocyst that was destined for the medical waste bag and turned those cells into a treatment for spinal cord injury speaks for itself. Editorial comment over.)
    Davies: What people must remember is that our test for iPS generated cell types is those same cell types generated from ESC. ESC is the gold standard.

    Question: why not use Decorin together with rehab on people now, while the complicated trials are being designed?
    Davies: I have a nondisclosure agreement that prevents me from telling you about a breakthrough we made 6 months ago . . . we're focused on the very first quality, top of the line treatment for sci.

    Question: what should we be doing now?
    DAvies: keep doing rehab, even if nothing seems to be happening. you're keeping circuits alive and you're going to need them.
    Horner: if i were designing a clinical trial, i'd be looking for a group of patients who had a similar profile, and that profile would include regular pt.
    Davies: we're going to need to look at a good record from rehab so that we have something to measure against . . .

  4. #24
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    I am so sorry we could not make it. Budget and time issues this year! Interesting stuff so far. I am a little concerned about the rehab./regular pt. issue. What if you can't afford this or your insurance does not cover it? What if you don't have access to pt. for sci? That is going to exclude me from trials?

    Thanks again for doing this Kate.

  5. #25
    Senior Member kate's Avatar
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    Breakout Ed Wirth

    The FDA said that for safety, a year followup is not long enough, and we agree.

    They had a woman in a different trial who missed her 6 and 12 month follow up visits, and died at 23 months (this was NOT an esc trial or an SCI trial -- it was a parkinson's trial)

    The FDA generally give you a problem, asks for your proposed solution, then lets you know if that's okay.

    What if the patient moves? They have to live within 2 hours of the center to get in. Also they've signed an informed consent form. Here are the risks, there are no known benefit to humans, etc.

    We give them 24 hours and then talk with them about all the issues. Every one of the centers is also allowed to modify the standard consent form as they see fit. if someone in Austin got injured tomorrow, they couldn't sign up for the trial until they were already inside the hospital site there.

    We'd like to know if our cells are efficacious at one month. We'd like to be able to give patients that much time.

    Are there exclusion criteria? It's up on clinicaltrials.gov, and as new sites are opened up, they'll be listed. Shepherd Center doesn't want to be listed there for fear that they'll be inundated with patients wanting to be in the trial.

    Richard Kessler at Northwestern has been helping us -- as long as 3 years ago we talked about the hardware issue. One way to deal is to place rods laterally instead of medially; another is not to use cross connectors; another is the way they put the screws in. Those simple things can make the patient a candidate. We're working through our surgeons to get the word around.

    MP really does work when given very early and in very high doses; sadly it has a bad rap. One of the things we don't talk much about is that even after an injury lots of white matter is intact, and that means doing injections can cause damage due to bleeding.

    The tissue damage is due to bleeding. Your cord is irreversibly damaged by bleeding, unlike your muscle, which just bruises.

    The secondary injury cascade begins when all those cells die, and lots of chemicals are released. They're what kill of the oligodendrocytes. It's like when a nuclear bomb goes off . . . if you're near you're dead, but if you're a distance away you'll survive a week or so before the radiation gets to you.

    Michael Fehlings in Toronto has been running a large scale trial that shows it's best to decompress within the first 24 hours if you can.

    How much time has been saved by the Geron trial? The main thing is not screwing it up. Something like that has already happened in stem cell research . . . Israeli boy who went to Russia, e.g. The main thing we can do is prove that there's no danger.

    Other companies may not have to play the 3-year guessing game with the FDA.

    Probably not.

  6. #26
    Senior Member kate's Avatar
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    Quote Originally Posted by momo3 View Post
    I am so sorry we could not make it. Budget and time issues this year! Interesting stuff so far. I am a little concerned about the rehab./regular pt. issue. What if you can't afford this or your insurance does not cover it? What if you don't have access to pt. for sci? That is going to exclude me from trials?

    Thanks again for doing this Kate.

    I just asked Phil Horner that question . . . he says in a perfect world, clinical trials, everyone who is chronic would get a six-month standardized therapy BEFORE they get enrolled. The main thing would be for people to take advantage of whatever is available to them and whatever they are able to do.

    I'd be glad to do a followup if you have one.

    k

  7. #27
    Senior Member kate's Avatar
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    Breakout Phil Horner

    How are you going to do standard rehab after a trial?

    There's a hot debate about what's appropriate care in terms of rehab. The primary goal would be to have something standard. You'd want every patient to be doing a routine and not to change that routine after injection of cells.

    When we go to efficacy, it's going to be really critical that we do the trials well, and honestly right now everybody is thinking about safety of cell transplants and not so much controlling the rehab.

    Woman says that she just went to a neuro rehab conference at the Shepherd Center and everyone is saying that both human and robotic training are effective, but only robotic training allows them to measure. And measurement is what shows efficacy, nothing else.

    And what about emotional health? How are you going to manage those or even know about what impact they have or don't have? The Parkinson's trials have been all over the place in terms of results, and part of that has to do with how hard it is to control all the things that would have to be controlled.

    Question about access . . . can't do it if there's no place. Shouldn't there be a whole network of little strip mall exercise places like Curves, where people could pay some minimum amount to be assisted?

    That would be amazing.

    Talking now about the Portugal surgery. Phil has asked the people in the room with sci to talk about their own decisions. Two people with 2-3 year old injuries say that they thought about it seriously. One of them tells a story about a friend who did go there and came home with an injured arm.

    man with new injury talks about going right to project walk, and his exercise regimen after that.

    Says that he was thinking of going to India or China or Mexico but chose to come here to w2w instead . . . now after listening all day has decided against going at all.

    Phil says that people don't realize anyone who has had any sort of non-FDA approved cell-based therapy has just added 10 years to the earliest date at which they can take advantage of new therapies. The reason is that they won't be eligible for a clinical trial of any kind, which means waiting for the full FDA approval, whenever that occurs.

  8. #28
    Quote Originally Posted by Leif View Post
    Thanks Kate - greate report. See you all tomorrow
    Leif,

    I am sorry I could not make it out to AZ for coffee..I hope you have a wonderful time!

    Mary
    1FineSpineRN

  9. #29

    A few photos from W2W

    The first is me and Leif
    The 2nd is Kate blogging
    The third is Leschinsky and her friends Jub with Dr. Young
    "Hope is like a road in the country; there was never a road, but when many people walk on it, the road comes into existence." Lin Yutang

  10. #30
    I was there. It was great. There was so much information I couldn't even get it all. Dr. Young and I chat on Facebook quite a bit so it was really nice to actually meet him. I went up to him and he looked at me and I said hello and put my hand out to shake his hand, and instead of shaking my hand, he gave me a big hug and immediately started talking to me like we had been friends for ages. It was really nice. He explains spinal cord injury in ways that I never thought of it. After the main conference, I went in for a smaller more personal conference where he explained that he doesn't believe in the scar tissue problem because the way he put it was that a lot of clinicians cut the spinal cord which ends up leaving scar tissue and rarely is any of our spinal injuries cut. It was really interesting. I'm going back tomorrow. Now that I know who everyone is, maybe I can meet you guys somewhere after the conference.
    C-5/6, 7-9-2000
    Scottsdale, AZ

    Make the best out of today because yesterday is gone and tomorrow may never come. Nobody knows that better than those of us that have almost died from spinal cord injury.

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