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Highlights and (My Reasons for) Hope from 2006

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    Highlights and (My Reasons for) Hope from 2006

    Highlights and (My Reasons for) Hope from 2006
    Wise Young, Ph.D., M.D.
    W. M. Keck Center for Collaborative Neuroscience, Rutgers University
    (Writing from the Hong Kong University where I am a visiting professor)

    With Christmas and a New Year coming, I thought that it would be appropriate for me to do a year-end summary of progress in the field of spinal cord injury. The following represent what I believe are some of the most important developments in 2006 that give me hope and why I believe that a cure for spinal cord injury is not only on its way but will arrive sooner rather than later. A very happy and merry holidays to all. Enjoy.

    Stem Cell Therapies

    Embryonic Stem Cell Research. From 2001-2006, President George Bush not only forbade the U.S. National Institutes of Health (NIH) to fund research on human embryonic stem cells derived after August 2001 but diverted nearly a third of NIH funds from cure and disease research to biodefense research. This has held back stem cell research for four years, a trend that has only recently begun to reverse. In 2006, California started funding human embryonic stem cell research, despite lawsuits that continue to prevent $3 billion of bonds for stem cell research (Proposition 71), approved by California voters in November 2004. By borrowing money from foundations, the California Institute of Regenerative Medicine (CIRM) awarded over $30 million of training grants in the summer of 2006, identified major resource centers that would serve stem cell researchers, and issued its two requests for "seed" and "comprehensive" research proposals. Governor Schwarzenegger and the California legislature approved a "loan" of $150 million to the Institute to begin funding of the research. I am part of the committee that reviewed 237 "seed" applications from junior faculty to study human embryonic stem cells. In January, we will be reviewing another lot of "comprehensive" grant applications from established investigators. I was impressed by not only the quality but also quantity of applications. From California, there were over 400 grant applications. The huge number of grant applications indicates that there is a real hunger for scientists to do stem cell research. The high quality of grants indicates that the best scientists are choosing to do research on the subject. The California stem cell initiative will double scientific studies of human embryonic stem cells in 2007. In 2006, there were only about 1000 studies. The California investment will be getting enormous bang for the buck. The November election of 2006 changed the power balance in the U.S. and there is a good chance for passage of the Stem Cell Research Enhancement Act to allow U.S. federal funding of human embryonic stem cell research. When that happens, I predict that NIH will get a huge influx of many grant applications to do the research. We will see an exponential growth of stem cell research in the coming year.

    Adult Stem Cell Research. Major breakthroughs have been made in adult stem cell therapy in the past year. In 1999, my friend and colleague Ira Black at the Robert Wood Johnson School of Medicine reported that bone marrow contained pluripotent stem cells that could make neurons. This was very controversial at the time and Ira was not able to develop reliable procedures for consistently isolating and producing neurons from bone marrow cells. In 2006, this has changed. Although many groups have now reported differentiating bone marrow stem cells into many kinds of cells, I would like to focus on one investigator. Mari Desawa is an Associate Professor in the Department of Anatomy and Neurobiology at Kyoto University. She has successfully grown neurons (and many other kinds of cells) from bone marrow cells. Mari not only developed procedures that are reproducible but successfully used the cells to repair brain and spinal cord, published in some of the best journals in the field. She is a very impressive researcher. I was having dinner with her recently and asked her whether she was good at growing plants. She looked puzzled and then brightened up. She says that she loves to cook. She is right. Growing stem cells is not unlike cooking. Bone marrow is a practical source of immune-compatible cells for transplantation. Mesenchymal stem cell research has now progressed to the point that most scientists are no longer arguing whether cells transdifferentiate. They are too busy trying to find out how and why cells transdifferentiate.

    New Jersey Stem Cell Initiative. The state of New Jersey passed a bill to spend $270 million building stem cell facilities in the state. Legislative leaders are committed to pass a bill to ask the New Jersey electorate in November 2007 to decide whether they want to fund $230 million over 10 years for stem cell research. While this amount of funding is small compared to the $3 billion that California will be spending, this is still a very significant funding by a state that houses over 50% of the therapeutics companies in the United States. Unlike the CIRM, which awards grants to dozens of institutions, the New Jersey Stem Cell Initiative will be investing in one major Stem Cell Institute of New Jersey and several smaller facilities in the state. The New Jersey effort also will focus on all stem cells, not just human embryonic stem cells, going where the best science takes us. On December 20, Governor Jon Corzine signed the bill into law and, along with other legislative leaders, committed to passage of a second bill to ask the New Jersey voters to approve a $230 million bond to fund stem cell research in the state. Yesterday, New Jersey Senate President Richard Codey requested and Governor Corzine supported his request to name the Stem Cell Institute of New Jersey after Christopher Reeve who had championed the bill. It is so fitting and I am very pleased.

    International Funding of Stem Cell Research. Progress is being made in funding stem cell research in other countries. For example, the Australian Parliament has decided allow human embryonic stem cells and even therapeutic cloning research. There was a fierce debate over this matter four year ago and the parliament decided to pass a law to allow embryonic stem cell research but not cloning for 3 years, and then re-visit the issue. The Australian experience is actually a very useful illustration of how the debate should be resolved. Rather than decide the future on the basis of inadequate information, they chose to postpone the decision until more and better information is available. Their decision is part of a stunning series of worldwide legislative reversals for opponents of human embryonic stem cell research. All this tells me that stem cell research is not a fleeting regional public fancy but a lasting world-wide commitment.

    Clinical Trials

    In 2006, several clinical trial developments have given me reason for hope. These have occurred despite the dearth of clinical trial funding from government and from the pharmaceutical industry in general.

    Cethrin. Cethrin is a blocker of the intracellular messenger Rho that mediates the inhibiting effects of Nogo and growth inhibitors. The company Bioaxone just completed a phase 1/2 clinical trial showing that Cethrin not only can be safely injected into the spinal cords of people after injury and is well tolerated but the patients apparently recovered more motor and sensory function than expected. About 31% of the patients converted from the ASIA A (complete spinal cord injury) to ASIA C (motor-incomplete spinal cord injury). This is a very strong result for a phase 1/2 trial. This is the first of the growth inhibitor blockers shown to be a feasible, safe, and possibly efficacious regenerative therapy for spinal cord injury.

    Fampridine. This drug, also known as 4-aminopyridine (4-AP), was reported by Acorda Therapeutics to have highly significant effects on locomotor speed and fatigue in people with multiple sclerosis (MS). On average, people with MS that received fampridine halved the time required to walk 10 meters and reported less fatigue in doing so. While one phase 3 trial alone is not sufficient to obtain approval by the FDA and Acorda will need to do another phase 3 clinical trial to confirm, it is important that fampridine has been shown to work in at least one demyelinating condition. It is the first drug therapy to improve function rather than just prevent functional loss in MS. For this trial, Acorda was also able to obtain an unprecedented agreement from the US FDA to accept what is called a "responder analysis" of treatment results. In such a trial, if some subjects in the treatment group that respond to the treatment (according to a pre-defined criteria) differ significantly from non-responders and controls, the FDA will accept the results as being significant. If this is not a fluke and the FDA continues to allow clinical trials to do this, this will have a dramatic effect on the field. Most drugs affect only a certain percentage of people. Being able to compare "responders" separately from all treated subjects would markedly reduce the number of patients that are necessary to show therapeutic efficacy in phase 3 trials.

    China Spinal Cord Injury Network. Although I am usually reluctant to extol the virtues of projects that I am involved in, I think that I would be remiss if I omitted ChinaSCINet from the list of my hopes because ChinaSCINet is not just my project but also the hard work of hundreds of families, scientists, and doctors. It is amazing that ChinaSCINet even occurred. At the beginning, everybody said that it was impossible, that Chinese doctors would not work with each other, that we would not be able to raise the necessary funds in Hong Kong, and that there is no clinical trial culture in China. Today, over 150 Chinese doctors and scientists are working closely with each other. They have agreed to adopt a single standardized neurological examination and dataset for spinal cord injury clinical trials. We have successfully raised the funds to support the network activities and we have developed a strong spinal cord injury clinical trial culture in China. In addition, all the centers have trained to do animal spinal cord injury studies so that they can offer "one-stop shopping" for preclinical as well as clinical assessment of therapies. The ChinaSCINet currently has 20 centers with capability to randomize as many as 3000 subjects with acute or chronic spinal cord per year. We are carrying out clinical trials to test lithium and umbilical cord blood mononuclear cells in chronic spinal cord injury. I hope that other countries, including of course the United States, will invest in clinical trial networks for testing spinal cord injury therapies.

    Peripheral Nerve Re-routing

    Peripheral nerve re-routing has not received much attention in the United States. However, recent presentations by investigators in China have convinced me that axons not only can grow when they are given a route to grow but they will go all the way and reconnect with the appropriate targets to restore bladder and other function. More important, it illustrates how the spinal cord is capable of adapting to completely new ways of functioning.

    Re-innervating the bladder. Dr. Chuan-Gao Xiao has been re-routing peripheral nerves from below the injury site to the bladder for over a decade. Although many studies in animals have shown that it is possible to re-innervate the bladder with functional restoration of bladder, few people were excited about this approach. Some thought that the function would not be normal. Others thought that having to stimulate skin to elicit bladder emptying is not the same as having voluntary bladder control. It also requires the sacrifice of at least one nerve below the injury site. I am much heartened by this work for three reasons. First, it is proof in humans that if you give axons a path to grow, they not only will take it but they will innervate a complex organ and restore function. Second, it is remarkable how good the function is. Dr. Xiao showed videos of patients at NYU with strong urinary streams going many feet. The people stimulated the part of the body to activate the re-routed nerve. Third, given the complexity of micturition requiring coordinated relaxation of the bladder sphincter and detrusor contraction to push the urine out, the videos tell me that re-routed peripheral nerves not only reinnervated the appropriate muscles but that the spinal cord was able to reorganize itself so that a part of the spinal cord that has never mediated micturition can do so. Dr. Xiao is carrying out the procedure in the United States and teaching U.S. surgeons how to do it.

    Re-innervating other muscles. Dr. Shao-Cheng Zhang at the Changhai Hospital in Shanghai has also been doing nerve rerouting from above the injury site to muscle and other organs for years. While nerve rerouting is not particularly new in China, the concept is relatively new for the United States and he has made several major advances recently that are quite significant. First, he has developed surgical procedures for sharing nerves without having to sacrifice the function of the donor nerve completely, by doing side-to-side instead of end-to-end anastomoses. Second, he has proposed use of early nerve re-routing to prevent atrophy of muscle that prevent functional return. Third, he has developed relatively non-invasive surgical techniques for doing nerve re-routing that significantly reduce the risk and complications of surgery. In the coming years, when surgeons around the world accept these advances, I believe that they will hail him as a pioneer in the field.

    Plasticity of the spinal cord. Functional restoration through peripheral nerve re-routing has implications far beyond just reconnection. To me, it is amazing that Dr. Xiao has been able to get functional micturition from re-routing nerves to the bladder. It not only means that the axons know what to connect to but that a very different part of the spinal cord is able to learn how to operate those nerves to get the bladder to perform a complex coordinated act of relaxing the bladder neck and internal sphincter (and, in males, an external sphincter as well), to contract the detrusor muscle to increase urinary pressure so that the urine would come out, and to maintain continence of the bladder between micturition. The part of the spinal cord that is traditionally thought to mediate micturition is Onuf's nucleus, located in the S1 spinal cord. The fact that nerves from other parts of the spinal cord can do so has enormous implications for the plasticity of the spinal cord. Likewise, the fact that Dr. Zhang can get the spinal accessory nerve or other nerves to operate the biceps or triceps, or even the hand, is amazing. Re-routed nerves can perform complicated and coordinated motor tasks. Finally, Dr. Xiao pointed out that many patients who received the re-routed nerves show improved anal continence and bowel elimination reflexes as well. If true, this is remarkable because anal reflexes are very complicated. For example, the anal canal possesses sophisticated continence mechanisms that can differentiate between gas, fluid, or solid stools. It allows the first to pass but is able to hold back the latter two until voluntary elimination. These results indicate that the spinal cord is much more plastic than we know and gives me confidence that when we get regenerating axons to the lower spinal cord, the plasticity of the spinal cord will allow them to function.

    Conceptual Therapeutic Advances

    Several years ago, the concept of combination therapies took a hold of the spinal cord injury field. It was a logical concept because we know that multiple obstacles obstruct regeneration in the spinal cord and it would be good to clear all the obstacles at a time so that the axons would have a clear path to reconnecting with neurons. For example, the Bunge laboratory at the Miami Project showed that the combination of Schwann cell transplants, rolipram (a phosphodiesterase inhibitor which raises intracellular cAMP level), and dibutyryl cAMP itself were effective in getting functional regeneration in rats after spinal cord contusions. However, the concept of combination therapy has become more sophisticated.

    Sequential therapies. Many people and scientists think that combination therapies must be applied at the same time. This may not be true. After all, because regeneration takes a long time and encounter different obstacles at different times, it may be possible or even desirable to deliver therapies sequentially when they are needed. While this is only conceptual right now because nobody has had much experience giving therapies sequentially in either animal or human studies, in my opinion, this is a major advance in our thinking. Why not build a bridge and get the axons started across the injury site first before administering the growth inhibitor blockers? It introduces the concept that not all therapies should be applied at the same time. It takes advantage of the knowledge that regeneration is a slow process that takes a number of years with different needs and obstacles at the beginning than at the end.

    Differentiated cell therapies. The possibility of stem cell treatment of the spinal cord has many people excited. The power of stem cells is of course the fact that they can make many different kinds of cells. But, how do the stem cells know what to do to repair the spinal cord? After all, stem cells are already present in the spinal cord and they are not sufficient or perhaps don't know what to do to repair and regenerate the spinal cord. Rather than putting in stem cells, scientists are pre-differentiating the cells to get the right kind of cells before transplanting them. One of the first indications that this is the right approach came from Davies, et al. (Source) who reported earlier this year that differentiating embryonic glial-restricted precursor cells to astrocytes before transplantation was effective in promoting growth of over 60% of ascending dorsal column axons into the center of the injury site and 66% of these axons continued to grow out of the injury site.

    Stimulating endogenous stem cells and neurotrophins. We often seem to forget that the spinal cord itself is a source of stem cells and neurotrophins. This year, the concept of using therapies to stimulate the spinal cord itself to produce more stem cells and to secrete more neurotrophins, rather than to implant the cells or give external neurotrophin, has taken hold of the field. This approach makes sense. Why put the cells or the growth factors in when the spinal cord itself can produce them? One of the first such therapies is lithium. Lithium has long been used to treat manic depression and its mechanism of action in depression is now believed to act by stimulating both stem cells and neurotrophin production in the brain. Physicians have long noted that lithium itself does not seem to have a direct anti-depressive effect and that it may take weeks before it begins to have an anti-depressive effect on patients. The delayed effects of lithium may well be due to its indirect mechanism of action. It may also have the added benefit of protecting the spinal cord and transplanted cells, as well a promoting the proliferation of the transplanted cells. Lithium is likely to be the first of a major class of therapies aimed at stimulating stem cell growth and neurotrophin production, and cell transplant survival and proliferation.

    In summary, there are many reasons for hope that there will soon be therapies to restore function in people with spinal cord injury. While the therapies are not yet here, the path towards these therapies is clear. California has begun funding human embryonic stem cell therapies in earnest. Adult stem cell research, particularly on bone marrow stem cells, has advanced significantly with widespread acceptance of the concept that bone marrow has pluripotent stem cells. New Jersey passed a $270 million bill to establish the Christopher Reeve Stem Cell Institute and other stem cell facilities. Other countries, such as Australia, are relaxing restrictions on stem cell research. I predict that there will be an immense outpouring of stem cell research next year due to increased funding from the states and a likely change of U.S. federal policy towards stem cell research. At the same time, there has been significant progress in getting some therapies to clinical trials. A recent clinical trial has reported the first successful application of the growth inhibitor blocker (Cethrin) to people with spinal cord injury. Likewise, Acorda Therapeutics recently announced positive phase 3 clinical trial results of Fampridine treatment of multiple sclerosis. The China Spinal Cord Injury Network has been formed and may encourage similar clinical trial networks in the United States and Europe. Recently reported results of peripheral nerve re-routing to improve bladder function and other functions in China have been impressive. Remarkable functional improvements associated with peripheral nerve re-routing not only indicate that axons grow long distances and connect to appropriate targets but the spinal cord is capable of tremendous plasticity. Finally, the field has achieved several major conceptual advances, including sequential therapies, differentiated cell therapies, and drugs that stimulate endogenous stem cells and growth factors.
    Last edited by Wise Young; 24 Dec 2006, 10:48 PM.

    Thanks Dr. Young


      Thank you so much Wise, your optimism is a very good Christmas gift to all of us. I hope you and your family have a great holiday.
      "Life is about how you
      respond to not only the
      challenges you're dealt but
      the challenges you seek...If
      you have no goals, no
      mountains to climb, your
      soul dies".~Liz Fordred


        Dr. Young, thank you for the SCI cure synopsis for 2006. It was very good reading. Happy Holidays.
        Step up, stand up for:

        'He not busy being born is busy dying." <Bob Dylan>


          You referred to the plasticity of the spinal cord. This is so mind-blowing, that a surgeon can place a nerve that had developed to do one thing close to an organ that has been for some reason denervated, and the nerve will grow and connect to the organ, and learn to do the correct job. I suppose that in principle this is what happens naturally during fetal development, but still my understanding is so limited that it seems like magic to me.
          Thank you for the review. There's a lot going on, and positive developments on many fronts.
          - Richard


            What a great Christmas present for every one in the CC community!
            I want to join in with the best of holiday wishes for you, Wise.
            Merry Christmas and a very Happy New Year


              Originally posted by Wise Young
              I believe that a cure for spinal cord injury is not only on its way but will arrive sooner rather than later. A very happy and merry holidays to all. Enjoy.
              These mere words are better than any gift I will receive for Christmas. Thank-you for your optimism and your unrivaled passion to cure spinal chord injury.

              Happy Holidays to you and your family.
              Birds Fly in Flocks, but Eagles Fly Alone...


                Yay for nerve grafts - a strong hope I have for chronics that's tangible!!!
                Roses are red. Tacos are enjoyable. Don't blame immigrants, because you're unemployable.

                T-11 Flaccid Paraplegic due to TM July 1985 @ age 12


                  Thanks and Merry Christmas to you and your family, Dr. Young.


                    Originally posted by dan_nc
                    Thanks and Merry Christmas to you and your family, Dr. Young.
                    The same from me, always nice to see your dedication. Thank you.


                      Come on Cethrin!


                        What ????? Is going on with Cethrin ? I called Bioxane a few times with no response ? Would love to get in the 3rd Trials...


                          Thank you.

                          Happy Holidays Dr. Young and everyone.


                            Excellent read Dr. Young.

                            Thank You and Happy Holidays
                            A good friend is someone who will come to bail you out of jail. A TRUE friend is the guy sitting next to you behind the same set of bars saying, "boy we sure f*cked up this time huh?"


                              thank you dr.young.
                              happy holidays and all the best to you and your family.