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  1. #1

    Question Dr. Wise, Help Please?

    As I read more and more through our information-filled forum, I become more and more desperate, and I think many of my peers feel this way as well.

    The threads detailing the cure options available in the past 2 years are long, full of side info and have many subjective views.

    As most of us are busy with their daily schedules, we haven't got enough time to track each therapy to the full and to make a full opinion about it.

    Confused among Dr. K and Dr. Deda in Holland and Turkey, Andrew's mystery in the US, Dr. Huang's procedure in China, Dr. Lima's of Portugal and the Korean stem cells lines.

    Personally I find myself in a dilemma, what is the real progress that we've got from each of these therapeutic options?

    We just want a moment of your time to discuss your personal feelings of what is going on on the cure front?

    We just want to know what direction are you in favor, which one is the most promising, what can we expect in the near (1-2 years) future?

  2. #2
    I will try to be brief. Let's select some therapeutic targets and see if any of the current trials come close to meeting these targets.

    1. Bridging the gap. Transplanted cells provide an environment that axons will grow on across the injury site: OEG, umbilical cord blood stem cells, bone marrow autografts, and Schwann cells.
    2. Growth factor: GDNF (preferably provided by the transplanted cells).
    3. Growth inhibitor blocker: Chondroitinase, Cethrin, Nogo blocker.
    4. Motoneuronal replacement: Embryonic stem cells, fetal stem cells.


    Bridging the gap. The site of spinal cord injury is a no-man's land and few axons regenerate across the injury site. Cell transplants may solve this problem but there are many choices. Of available cells for transplantation, the most clinical experience has been with fetal OEG with over 600 cases in Beijing alone. Fetal OEG cell transplants appear to be safe and produce some functional improvement. The work in Portugal suggests that nasal mucosa transplants may also be safe but information about function recovery is limited. In Russia, several groups have been transplanting fetal neural stem cells for over a decade but evidence for recovery is not yet available or credible. While bone marrow stem cell autografts are feasible and immune-compatible, there is not yet convincing evidence for regeneration associated with bone marrow transplants in either animal or human trials. In Zhengzhou (China), one group transplanted bone marrow mesenchymal cell autografts into 180 patients with apparently limited beneficial effect. Other autograft options are available: Schwann cells and enteric glia. The fact that the cell transplants are not producing substantial functional recovery is not necessarily bad news. Even in animal studies, cell transplants alone generally have not produced substantial recovery. The goal of the transplants is to provide a bridge and other treatments may be necessary to promote regeneration across the bridge. Also, a "permanent" bridge may not be necessary. In fact, it may be desirable for the bridge to be replaced by endogenous cells after the axons have grown across the injury site.

    Growth factor. Animal studies suggest that growth factors are needed to stimulate axonal growth. There are of course many growth factors and there is insufficient time to discuss all of them. At the present, the most promising and safest growth factor is glial-derived neurotrophic factor (GDNF). GDNF has been given to human (Parkinson's disease) and animal models with a reasonably good safety record. The source of the GDNF was unfortunately recently shut down (Amgen) but many cells (including OEG and neural stem cells) produce GDNF. We have animal data indicating that lithium will stimulate OEG and stem cells to produce GDNF. Cellular delivery of GNDF may be the most efficient and safest way of providing growth factor to the spinal cord. We are thus studying ways to increase GDNF secretion by other cells, including umbilical cord blood and bone marrow stem cells. Note that both bone marrow and umbilical cord blood stem cells may secrete yet unidentified growth factors. It is possible to use gene therapy to modify transplanted cells or the spinal cord to increase growth factor secretion but these approaches will require much work to establish safety and efficacy.

    Growth Inhibitor Blocker. At least two growth inhibitors have been shown to prevent regeneration in the spinal cord: chondroitin-6-sulfate proteoglycan (CSPG) and Nogo. Much animal data suggest that chondroitinase and Nogo blockers will overcome these two inhibitors. Cethrin may be able to overcome both by blocking the Rho signal the mediate axonal growth inhibition and is currently in phase 1 trial. An anti-Nogo antibody (IN-1) is going into phase 1. There is currently no clinical grade chondroitinase available and, while there is substantial animal experience, we have no clinical experience with application of chondroitinase to human spinal cords. One animal study suggests that rolipram and dibutyryl cAMP combined with Schwann cell transplants will overcome the inhibition but more animal studies and clinical experience is needed. The results of the trials showing safety and efficacy of chondroitinase and Nogo blockers are needed.

    Neuronal replacement. If people have lost motoneurons (i.e. lumbosacral injuries), neuronal replacement may be necessary. At the present, only two sources of cells have been shown to replace neurons in the spinal cord: embryonic stem cells and fetal neural stem cells. In order for the cells to survive, they must be immune-compatible. This more or less rules out the fetal neural stem cells because there are simply not enough fetuses to allow immune matching. This leaves only cloned embryonic stem cells. There has been much progress with cloned human embryonic stem cells in Korea and clinical trials are likely in the near future.

    In summary, while there is much excitement surrounding OEG, bone marrow, and umbilical cord blood transplant trials going on in China, Portugal, Turkey, and Korea, the data so far suggest that these transplants will produce limited improvements. While OEG have been reported to remyelinate and regenerate injured spinal cord in animals, clinical experience to date suggest that OEG transplantation alone produces only modest improvements in human. Animal studies of bone marrow transplants suggest that they will stimulate remyelination but evidence for regeneration and recovery is still very limited. Experience with bone marrow stem cell transplants in China suggests little or no improvement to date. Likewise, there is no credible evidence from animal studies and only one anecdotal human case suggesting improvement due to umbilical cord blood stem cell transplants. So, in my opinion, none of the clinical trials meet the therapeutic targets of providing a cellular bridge, growth factors, and growth inhibition blockade. This is the main reason I have been urging people to wait and why we have been working hard trying to get a clinical trial network going to test combination therapies in the ChinaSCINet and in the United States.
    Last edited by Wise Young; 08-25-2005 at 07:56 AM. Reason: corrected grammatical errors

  3. #3
    Dr.Young, you say that recovery from bone marrow transplants is very limited in animals, but didn't the SCSA have results of excellent recovery in chronic rats using bone marrow stem cells?

  4. #4
    Quote Originally Posted by zokarkan
    Dr.Young, you say that recovery from bone marrow transplants is very limited in animals, but didn't the SCSA have results of excellent recovery in chronic rats using bone marrow stem cells?
    The recovery studies that I have seen have been with demyelinated rat spinal cords (Kocsis, et al.). I am not sure what SCSA studies you are referring to. Are you thinking of the Jean Peduzzi work? The last I heard, she was working with nasal mucosa OEG. The only published study that I am aware of which shows recovery from spinal cord injury in rats using bone marrow transplants was the study where Mark Tusczynski used a combination of bone marrow and growth factors. Wise.

  5. #5
    Since yopur talking about bone marrow
    Dr. K said in his interview that he was not using CD44+ cells. What other cells would he be using?? Also he said the bone marrow hasintracellular compounds that dissolves scars. What would this be?

  6. #6
    Senior Member Schmeky's Avatar
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    Thanks for your overview Dr.Y,

    Even though much progress has been made, it appears as though there is still a long way to go, requiring many years to get there.

    The China SCINET will be a proving ground in the next several years, hopefully somthing will eventually prove fruitful.

  7. #7
    Quote Originally Posted by richwelsh63
    Since yopur talking about bone marrow
    Dr. K said in his interview that he was not using CD44+ cells. What other cells would he be using?? Also he said the bone marrow hasintracellular compounds that dissolves scars. What would this be?
    Richwelsh63, there is currently no specific marker for mesenchymal stem cells. There was a recent report of three markers that seem to be able to track hematopoietic cells. Although CD44+ has been suggested to be a marker of mesenchymal stem cells and may help enrich the population for mesenchymal stem cells, it is not a specific marker. To my knowledge (unfortunately the specific isolation or concentration procedure used by C4H is proprietary), it is not clear what cells are being transplanted in Turkey. By the way, not only have the procedure not be been disclosed but there is no description of the cells that are transplanted, their markers, or their behavior cultured further.

    Wise.

  8. #8
    Senior Member poonsuzanne's Avatar
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    Dr. Young,

    Thanks for illustrating the SCI therapeutic targets again in details. Please help us to get them on human clinical trials ASAP.

    Suzanne
    Suzanne

  9. #9
    Quote Originally Posted by poonsuzanne
    Dr. Young,

    Thanks for illustrating the SCI therapeutic targets again in details. Please help us to get them on human clinical trials ASAP.

    Suzanne
    Suzanne, thanks. Wise.

  10. #10
    Dr.Young, the bone marrow stem cell studies that the SCS Australia did were done by the following researchers: Stuart Hodgetts, Paul Simmons, David Haylock and Giles W Plant. The results were also presented at the National Stem Cell Center in Australia. They are now investigated ways to further enhance recovery by combined the BMSC with Decorin and doind multiple injections of BMSC in the spinal cord, first at 7 days, then after one month. The use of Decorin is only going to be used on chronic rats.

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