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Thread: A Question Dr Wise

  1. #1

    A Question Dr Wise

    Dear Dr Wise
    It is going to star next moth the trial in ChineSciNet, (i m sure)and what i read this trial will improved bladder and bowels.
    what results you hope to gain?
    This trial will restore functions?
    Best Regards

  2. #2
    Quote Originally Posted by carlosar View Post
    Dear Dr Wise
    It is going to star next moth the trial in ChineSciNet, (i m sure)and what i read this trial will improved bladder and bowels.
    what results you hope to gain?
    This trial will restore functions?
    Best Regards
    Carlosar,

    I do't know what the results will be. We are hoping that the treatment with umbilical cord blood mononuclear cells will improve motor and sensory function, and possibly walking. Those are the outcome measures that we have chosen for the study. While we are not doing formal bladder studies, we are collecting SCIM data which indicates the kind of bladder and bowel care the patient uses. Please note that there will not be enough patients in the phase 2 trial to provide convincing statistically significant results unless of course the improvement is very large. If the study shows feasibility and safety of the different doses of cell transplants and some efficacy, we will proceed to a pivotal (phase 3) trial to obtain convincing evidence of efficacy.

    At the present, we are doing our very best to ensure that the cells meet all FDA standards and will also be ready to go to clinical trial in the United States.

    Wise.

  3. #3
    Thanks a lot for your answer and the best o the best succes for the trial

  4. #4
    Quote Originally Posted by Wise Young View Post
    Carlosar,

    I do't know what the results will be. We are hoping that the treatment with umbilical cord blood mononuclear cells will improve motor and sensory function, and possibly walking. Those are the outcome measures that we have chosen for the study. While we are not doing formal bladder studies, we are collecting SCIM data which indicates the kind of bladder and bowel care the patient uses. Please note that there will not be enough patients in the phase 2 trial to provide convincing statistically significant results unless of course the improvement is very large. If the study shows feasibility and safety of the different doses of cell transplants and some efficacy, we will proceed to a pivotal (phase 3) trial to obtain convincing evidence of efficacy.

    At the present, we are doing our very best to ensure that the cells meet all FDA standards and will also be ready to go to clinical trial in the United States.

    Wise.
    Dr. Young,

    Is this the trial you are discussing? http://www.chinascinet.org/index.php...125&Itemid=165

    If you have the time I have a couple questions. As you may have guessed from my username I sustained a burst fracture to the T8 vertebrae. There was a lot of structural damage to my spine, so much so that the surgeon had difficulties putting screws into the T8 area (the T9 and T7 were relatively undamaged). Is a treatment like this viable for someone like me? I worry that since along with nerve damage I have a good amount of, for lack of a better word, bone damage and because of that a treatment that regrows nerves will not help me. Would the neurosurgeon who put my spine back together left a path for the nerve to regrown in anticipation of a cure down the line? Worst case would it be possible to re-break my back and create a route for the nerve to re-attach?

    Thanks,
    Tom

  5. #5
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    Quote Originally Posted by t8burst View Post
    Dr. Young,

    Is this the trial you are discussing? http://www.chinascinet.org/index.php...125&Itemid=165

    If you have the time I have a couple questions. As you may have guessed from my username I sustained a burst fracture to the T8 vertebrae. There was a lot of structural damage to my spine, so much so that the surgeon had difficulties putting screws into the T8 area (the T9 and T7 were relatively undamaged). Is a treatment like this viable for someone like me? I worry that since along with nerve damage I have a good amount of, for lack of a better word, bone damage and because of that a treatment that regrows nerves will not help me. Would the neurosurgeon who put my spine back together left a path for the nerve to regrown in anticipation of a cure down the line? Worst case would it be possible to re-break my back and create a route for the nerve to re-attach?

    Thanks,
    Tom
    t8burst,

    Your spine (the bony part) has probably been fixed with bone graft from your hips, titanium plates and screws and/or mesh cage while preserving the openings/empty space needed for the cord and roots. The spinal cord passing through the hollowness within the spine is contused/bruised but protected as-is inside the dura. If I remember right from Dr. Young's posts, axon damage is more usual than neuronal loss at the T8 level. Regenerative therapies aim to grow axons (nerve fibers) through the injury site rather than other therapies which replace lost neurons (of course the new neurons have to grow axons and make the right synaptic connections). Regenerative therapy for you would work on your spinal cord at the T8 level. I am sure when the therapies are ready, you would be a candidate for cure/treatment just like the rest of us.

  6. #6
    Quote Originally Posted by t8burst View Post
    Dr. Young,

    Is this the trial you are discussing? http://www.chinascinet.org/index.php...125&Itemid=165

    If you have the time I have a couple questions. As you may have guessed from my username I sustained a burst fracture to the T8 vertebrae. There was a lot of structural damage to my spine, so much so that the surgeon had difficulties putting screws into the T8 area (the T9 and T7 were relatively undamaged). Is a treatment like this viable for someone like me? I worry that since along with nerve damage I have a good amount of, for lack of a better word, bone damage and because of that a treatment that regrows nerves will not help me. Would the neurosurgeon who put my spine back together left a path for the nerve to regrown in anticipation of a cure down the line? Worst case would it be possible to re-break my back and create a route for the nerve to re-attach?

    Thanks,
    Tom
    Tom,

    I hope that it will not be necessary to "re-break" your back in order to get recovery. The vast majority of people who have had spinal cord injury still have a continuous spinal cord. [Note: only very rarely do people have a transected cord where two ends of the cord have been separated.]

    The injury site is not a particularly hospitable place for axonal growth. Axons are the nerve fibers of individual neurons. Axons communicate the signals over long distances and the part of the axon that has been separated from the cell body dies. Therefore, axons must regrow all the way from the injury site back to where they originally connected to restore function.

    If the injury is severe, the normal spinal cord tissue have been destroyed replaced by glia and other cells that do not provide much growth factors and directional cues for axonal regrowth across the injury site. Glia are responsible for segregating the central nervous system from other tissues in the body.

    So, for example, glia line the blood vessels to form a barrier called the blood brain barrier. Glia line the surfaces of the spinal cord and the brain. They may line the edges of the spinal cord injury site. When they do this, they secrete an extracellular material called chondroitin-6-sulfate proteoglycan (CSPG) which demarcate the margins of the central nervous system. CSPG stops axon growth.

    There are several ways of getting axons through regions of CSPG. One is to bridge the regions with cells that are conducive to axonal growth. That is one of the reasons why we inject cells into the spinal cord at the edges of the injury site in our clinical trials. The other is to use bacterial enzyme called chondroitinase (sometimes called Chase), which breaks down CSPG. For example, a single injection of chondroitinase into the spinal cord will clear CSPG within 2 cm of the injection site for several weeks.

    Regeneration requires growth factors. In particular, three growth factors are known to stimulate regeneration of the spinal cord. These include neurotrophin-3 (NT3), nerve growth factor (NGF), and glia-derived neurotrophic factor (GDNF). NGF was the first axonal growth factor that was discovered and stimulates sensory axons to grow. NT3 is an CNS neurotrophin and is known to stimulate spinal axons to grow. GDNF is a general growth factor that is secreted by glial cells.

    We recently discovered that lithium stimulates umbilical cord blood mononuclear cells (UCBMC) to secrete large amounts of neurotrophins, particularly NT3, NGF, and GDNF. UCBMC of course comes from umbilical cord blood that is banked and can be HLA-matched to people so that the cells are not rejected. In animal studies, we have seen that transplanted UCBMC do not elicit a glial response from surrounding spinal cord cells, suggesting glial cells treat the cells like they are from CNS. [Note: in contrast, if you inject fibroblasts or skin cells into the spinal cord, glial cells will wall off these cells].

    So, we have proposed to transplant UCBMC into the spinal cord at the edge of the injury site, using a special MRI method called diffusion tensor imaging to show where the edges of the spinal cord are located. After the cells are transplanted, we then give the patients oral lithium twice a day for six weeks. We have shown in animals that lithium strongly stimulates UCBMC to grow and to secrete NT3, NGF, and GDNF.

    We have conducted two trials already. The first one gave lithium to 10 patients with chronic spinal cord injury for 6 weeks, showing that the treatment is safe. The second trial randomize 40 patients with chronic spinal cord injury to a six-week course of lithium or placebo. We wanted to make sure that the treatment is not only safe but would not cause any problem such as increase in neuropathic pain. The trial (not yet published) indicated that lithium did not improve motor or sensory scores but significantly reduced neuropathic pain scores. The latter was a relief because we were concerned that lithium might increase neuropathic pain. Instead, it seems to reduce neuropathic pain.

    The current clinical trial that we are doing in Hong Kong is a phase 1/2 trial where we are giving increasing doses of UCBMC into the spinal cord around the injury site. We do not know many cells to give and thus chose to assess the effects of giving 1.6 million, 3.2 million, and 6.4 million cells into cord surrounding the injury site. We will then couple the highest "safe" dose of cells (i.e. the dose that does not cause neurological loss) with a single bolus of high-dose methyprednisolone (a steroid that many investigators have now shown will improve survival of transplanted cells). Then we will combine the cell transplant with methylprednisolone and then a 6-week course of lithium.

    If all the of above turn out to be safe and, hopefully, improve some function in the patients, we will then go ahead to do what is called a pivotal phase 3 trial to test the efficacy of the therapy in large numbers of patients. We are planning to test the therapy in 400 subjects in China, where all 400 will receive the cell transplants and randomized to a 6-week course of lithium or placebo. There are three possible outcomes to the trial. If neither therapy improves function in the patients, compared to pre-treatment levels, we will conclude that neither are effective and recommend against the use of umbilical cord blood cell transplant treatment of spinal cord injury. If both therapy improves function, we then need to carry out a further trial to show that the surgery alone is not responsible. If the transplant plus lithium works better than transplant alone, we will be able to strongly recommend use of the combination therapy for chronic spinal cord injury.

    Because the therapy is intended to regenerate long tract axons, we are limiting the trial to subjects who have injuries from C5 through T10. However, if the treatment is effective, we will extend the trials to include subjects that have injuries from C1 through C4 and below T10. In the initial trials, we are also limiting the subjects to adults from 18 through 64 years. We are planning separate trials to examine the effects of the treatment on children (age 8-17) and older adults (64-80).

    Unfortunately, we have not been able to test the combination therapy in animals. The best and most reliable spinal cord injury models at present is the rat contusion model. Unfortunately, it is difficult to get umbilical cord blood from rats, particularly blood that is HLA-matched so that the cells would not be rejected. Most of the studies of umbilical cord blood transplants to the spinal cord have transplanted human umbilical cord blood cells into rats. When one transplants human cells into rats, one must use immunosuppression, such as cyclosporin. To our surprise, we found out that cyclosporin completely blocked the effects of lithium. For example, in the presence of cyclosporin, lithium does not stimulate umbilical cord blood cells to produce neurotrophins.

    On the other hand, both umbilical cord blood and lithium are well-known and safe therapies. Umbilical cord blood has been transplanted into over 20,000 patients since 1990 to treat a wide variety of hematological disorders and to replace bone marrow after cancer chemotherapy. We know that the cells will survive when HLA-matched and there have been no reports of tumors associated with cord blood cell transplants.

    Lithium likewise has a long track record of use in humans. Used for over 100 years, it was one of the first drugs approved by the FDA in the early 1970's and is still the first and best therapy for manic depression. About 3% of the population in the United States suffer from manic depression and about half take lithium for a lifetime. Lithium not only stimulates transplanted cells but also stimulates endogenous stem cells in the brain. For example, several studies have shown that people with manic depression who take lithium have significantly more neurons in parts of their brain than people who don't take lithium. I have published a review of the literature of lithium effects of stem cells of the bone marrow and brain. It is attached.

    We therefore chose to study these two treatments in the first clinical trials for ChinaSCINet and SCINetUSA. To obtain a best possible source of umbilical cord blood for the trial, we are working with Stemcyte, a company that has a substantial track record of successful use of umbilical cord blood treatment to cure people. We developed a method of isolating, purifying, and shipping mononuclear cells. We carried out the safety studies of lithium. In the next few months, we will know the safety, feasibility, and possible efficacy transplanting umbilical cord blood cells into the spinal cord. In 2011, we are hoping to initiate phase 3 trials of UCBMC ± lithium.

    If the trial shows that UCBMC+lithium regenerates the spinal cord and improves recovery, that would of course be great. If the trial shows the therapy is not effective, we then will recommend against the therapy and go on to test many other therapies that are waiting in the wings for clinical trials. Our goal is to test the most promising therapies of chronic spinal cord injury.

    Wise.

  7. #7
    Thank you Dr. Young this is very helpful. I have read and heard the information that you have presented various times before but this summary is clear and easy to comprehend.

    I have one question about the “10% rule”. I apologize for my layman understanding but from what I can discern from some of your previous posts is that we only need about 10% of our spinal cord to achieve locomotion. Is this particular 10% in a certain area? Is it 5% gray matter? 5% white matter? Is the 10% located more on the ventral portion of the cord? I'm currently taking a course in behavioral neuroscience and I briefly like to present a short segment on the functions of spinal cord/regenerative theories to my class–but I'd like to make sure that I have the correct information before presenting. Thank you in advance.
    Chaz

  8. #8
    Dr Young, I just read your attached file. I am wondering, if I read your attachment correctly, why are not all Alzheimers patients on a course of lithium? My dad has been diagnosed with early stages of it and wonder why this is not happening.
    Thanks

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