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Thread: The Stem Cell Meeting-Geron's hESC Clinical Trial

  1. #11
    Great write up John, Okarma is a great guy and very progressive. I have been following Geron for about the last 8 years. They have made huge inroads in cancer research also with GRN163.

  2. #12
    Senior Member kate's Avatar
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    Quote Originally Posted by john smith
    Their upcoming hESC trial on SCI and certain scientific breakthroughs with regard to ESC science. Everyone is watching. Should this clinical trial be successful, the entire field of ESC research will change.

    • Finally, he concluded by saying the field of regenerative medicine will arrive only when a therapeutic solution is demonstrated.

    He knows what is riding on the upcoming trial; literally the reputation of Geron. Steven Edwards has interviewed Okarma and may have additional details about the trial and the purported breakthroughs.
    Wow, thanks again and again. Steven, do you know the time frame? If the trial begins in the 4th quarter of this year, when will we have a feel for what constitutes "success?" What will be sufficient to demonstrate a therapeutic solution?

    Finally, for him, yeah-- what's riding on the upcoming trial is the reputation of Geron . . .for us it's a whole lot more.

    I'd love to have a look at the graveyard of your unpublished op/eds!

  3. #13
    Quote Originally Posted by lynnifer
    I hope we hear the eventual how and why of the above.
    To 2, are they contaminated:

    Better than that. Not only all-human, it's all defined chemically. So there's no serum in it. There's no conditioned medium that has undefined materials in it. So it's very squeaky clean, as is the differentiation process now done under good manufacturing practices (GMP) here.

    We've got the world's only GMP master cell bank of human embryonic stem cells with lines that are fully qualified for human use which, by the way, are two of Bush's approved lines. So the stuff you hear published that all of those lines are irrevocably contaminated with mouse materials and could never be used in people -- hogwash. If you know how to grow them, they're fine.

    To 3:

    There is the tumorigenesis issue and that comes from the fact that a large number of undifferentiated human embryonic stem cells, if allowed to aggregate in vivo -- in other words form a clump in a muscle of an animal -- will form what’s called a teratoma which is a benign but uncontrolled growth. It’s not cancer but it’s like a mole, and it’s how embryonic stem cells were proven to be pluripotent because if you just let the embryonic stem cells sort of do what it wants to do on its own, it will form this mass that has cells and tissues of all three germ layers in it.

    The obvious concern has come that, well, okay, we obviously have eight different manufacturing recipes that turn undifferentiated embryonic stem cells into the therapeutic cell type that we inject into the patient.

    OPCs, or oligodendrocyte progenitor cells, are one of those eight, and we know that in them, in that final prep there are no undifferentiated embryonic stem cells left over because the most difficult thing for us to do was to learn how to scaleably grow the undifferentiated stem cell starting material en masse but without letting it differentiate.

    These cells want to run out the barn door and turn into differentiated functional cells, so we have to learn and define the culture conditions carefully that enable us to allow them to replicate but not differentiate so as soon as we take our master cell bank cells out of that environment and start putting them down one of these eight different recipes, they’re off to the races, so we really don’t see undifferentiated cells in any of these preps.

    Nevertheless, we are rigorously testing whether over 12 months some undetected rogue cell could form a teratoma in the spinal cord of these animals. So, in addition to simply putting the OPCs into spinal cord injured animals and following them for tumors every year, in parallel to that we take the same OPC prep and deliberately contaminate it with undifferentiated living human embryonic stem cells to see what is the threshold of “contamination” that would be required to generate a tumor in an animal to assure ourselves, our docs, the patients and the FDA that our release specs are sufficiently sensitive to -- run after run after run detect -- and reject a run if we were to find that level of undifferentiated stem cells in it.

    That’s all in place and frankly we have not yet seen any tumors because it turns out that one of the steps that we use to harvest the OPC cell prep, actually prevents even added undifferentiated stem cells from forming a tumor in these animals so while the data are not yet finished, you know, all the studies are not in, we’re getting increasingly confident that this issue of teratomas is really a non-issue both because of how we treat the cells generally and the degree of purity or absence of undifferentiated rogue cells contaminating our final preps.

    To 4:

    It turns out that the undifferentiated embryonic stem cell and the differentiating cells that we make and put into animals are not recognized by the human immune system and we published this last year. It's a striking finding.

    If I were to mix my blood with yours and yours with mine, my immune cells in that blood test would react against you because we're different HLA tissue types. As would you react to me and that's basically what happens if you were to take a kidney transplant from me or vice versa which is why organ transplants are traditionally associated with for life high dose immune suppression. These are allografts, in that the cells that we're gonna put into your spinal cord are made from what would have been an embryo with a different tissue type from yours so you're right to ask, well will I need immune suppression. So, to our surprise, when we mix undifferentiated embryonic stem cells with people's blood with a different tissue type, they don't react to them. Moreover, in that example of your blood mixed with my blood, if we drop undifferentiated embryonic stems cells into that test tube, those cells would stop your body from recognizing me and vice versa, me from recognizing you. Moreover, the differentiating cells including the OPCs that we're talking about here, are negative in those same aspects.

    Now, what's that all about? Well, you've got to go back to the source of the biology and spend a little bit of time talking about the immunology of embryo implantation because that process is no different than an allograft transplantation into a woman's uterus because the embryo, with respect to the mother, is an allograft. It has mother and father tissue antigens so the question arises why doesn't the pregnant woman immunologically reject that implanted embryo and they never do that and the reason is the blastomeres in the blastocyst, those are the cells from which embryonic stem cells are derived have learned how to create an immune tolerant or an immune protective region in the uterus that prevents mothers' T cells from recognizing and killing that implanting allograft and, lo and behold, the embryonic stem cell has retained that capability so there's something in the membrane of both the undifferentiated stem cell and the differentiating cells we make from them that prevents the T cell which recognizes its alloness from reacting to it so the T cells don't activate so that suggests that for all of these therapies, whether it's OPCs into the spinal cord, cardiomyocites into the heart, islets into the liver, whatever, we will not need high dose for life immune suppression. Now with the particular case of the oligodendrocyte spinal cord injury opportunity, there's a further safety factor because once the injury heals, you are once back into the protected site of the central nervous system which is an immune privileged site further reducing the likelihood of immune detection of these OPCs. Nevertheless because we want to test one variable at a time, in the clinical protocol we will cover the patients with low dose cyclosporin for about three months and then withdraw it by which time the lesion should be healed and there should be no egress of any immune cell into that spinal cord lesion.

    Now, that's sort of the near term biology? There is a second generation approach that we'll be announcing later this year which should completely eliminate the need for any immune suppression for any of these cells and that has to do with a way to immunologically tolerize you or me to any of the cells made from a particular stem cell line and here's how this works -- and this can only be done with embryonic stem cells because these are the only stem cells that are pluripotent, that you can make all cell types of the body from each of our lines so one of the cell types that we know how to make are immune cells and specifically these are dendritic cells and there's a certain kind of subset of a dendritic cell that when given to you, if it came from my body, would actually make you tolerant immunologically to any organ or cell from me that goes into your body. This is new biology. So imagine now, embryonic stem cell line A from which we make that dendritic cell, I give that to you and that makes you immunologically tolerant to any cell type I make from that same stem cell line and give to you so the ultimate configuration here for all these cells types is that you first get the tolerizing cell from the embryonic stem cell line in question and then you get the therapeutic cell type. Now that work needs to be modeled in animals and proven rigorously so it's not ready for human experimentation any time soon but I just wanted to give you the whole rollout of the technology advance that: a) reassures us in the near term that we are not going to be putting patients with acute spinal cord injury on high dose immune suppression for life and b) coming around the corner, there is a permanent solution to that problem.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  4. #14
    Quote Originally Posted by kate
    Wow, thanks again and again. Steven, do you know the time frame? If the trial begins in the 4th quarter of this year, when will we have a feel for what constitutes "success?" What will be sufficient to demonstrate a therapeutic solution?
    They released new financials last week, so there may be an update in there. I'm trying to get the replay of their webcast to find out.

    The final decision rests with the FDA, though. Last April Okarma said this:

    We will complete our IND-enabling studies, which are now in process and still on track, and file our IND during the fourth quarter of this year, assuming the preclinical data continue to go well. That starts a 30-day review clock by the FDA, who then has 30 days to either accept our IND and allow us to proceed or, at that point, they have questions that we must answer before we can begin. We are on track for that. So, assuming they bless the IND, we would hope to be in the clinic in the first quarter of (2007).
    The FDA apparently didn't like them yet.

    As far as results, they'll be testing complete injuries first, so it may be a while. Their animal model was of an incomplete injury.

    We start with complete patients because they have no hope of recovery and we want to offer them something. We're starting with thoracic lesions because there's no significant impact for the patient should we see toxicity go from, say, a T3 to a T2 lesion. If we had started with cervical complete lesions and went from C4 to C2, that would be significant because we would reduce respiratory drive.

    We're turning every single stone over that we can to reduce -- if not eliminate -- the risk to these patients who volunteer to get the cells for the first time. Once we go through the initial safety cohorts ... then we start looking at incomplete lesions. For all these patients, the efficacy is based on three simple principles: Do we restore sensation in any way or conversely reduce neuritic plan? Do we change bowel or bladder control? Do we see patients enjoying some degree of local motor recovery?

    All of these things are monitored by America Spinal Injury Association, which have been developed to follow patients with incomplete lesions who can respond modestly to intense physical therapy. All of those endpoint measures are all validated and ready for us to use. We didn't have to invent anything.

    Our fondest hope is that, even in cases that have no hope of spontaneous recovery, we actually provide value. Now that may not happen. We may not see any responses in the first cohorts of patients who have complete lesions, which is why we're progressing thereafter to patients with incomplete lesions which resemble more closely the animal model, which is where the excitement began. Those animals are models of incomplete lesions. But for reasons of ethics and safety and appropriateness, we can't start with patients who resembled the animal model. You have to start way upstream.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  5. #15
    Senior Member spidergirl's Avatar
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    Quote Originally Posted by john smith


    The ESC line being used is among those few in existence at the time of President Bush’s executive order of August 2001. They are not tainted by mouse feeder cells. Dr. Okarma attests that Geron has proven the scalability of ESCs and has produced glial cells capable of treating the next 22 years of acute injuries. Even to a layman, such as I, that is a remarkable scientific achievement and is exactly the kind of basic science research the NIH should be funding.
    This is outstanding and I would be so happy for people who have no clue that they are injured yet to be able to get a treatment in the hospital immediately following their injury.


    Quote Originally Posted by john smith
    I did speak with him briefly following his speech. I asked if Geron had anything in the works for chronic injuries. He said no but that if this trial is successful, then other research would likely follow.

    John
    Likely to follow......? This is sad and disheartening to read. Being in California, I think that I need to, and others who live here need to force the chronic research/cure. There is no excuse.

  6. #16
    Likely to follow......? This is sad and disheartening to read. Being in California, I think that I need to, and others who live here need to force the chronic research/cure. There is no excuse.

    Posted by spidergirl
    Cheryl;

    I think this gets to the crux of Okarma's speech. Remember the title: Navigating Commercialization. Trials are very expensive, the research preceding the trial also takes time and money. The problem for biotechs is how to get from concept to product without going bankrupt. The legacy of the Bush policy is this kind of stutter-step science.

    Bush, a businessman, knew very well that he was gutting the field of regenerative medicine back in 2001. He got credit for being the first president to allow research into ESCs while the scientists and biotechs lay bleeding to death on the side of the road due to his restrictions.

    It is possible that Geron has something in the works for chronics, in spite of Okarma's statement to the contrary. He may not have felt it appropriate to comment. I know Keirstead has alluded to chronic research in year's past. A representative of Geron will be a featured speaker at the Working 2 Walk Rally in April. We can ask him.

    Steven;

    Thank you for the technical info on the science. Regardless of what happens with the clinical trial, Geron has accomplished some amazing things. Their discoveries will matter as we go forward.

    John
    "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

  7. #17
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    Thanks John. I believe this is important.
    Quote Originally Posted by john smith
    • He explained the conventional paradigm of scientific research that works: Academic research funded by the NIH leads to Industrial product development by private companies, which leads to patient therapies.
    Collaboration projects for therapies (read SCI cure) between Academia, Federal and Private corp. would have been good here.

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