Holiday Hopes for Spinal Cord Injury

Holiday Hopes for Spinal Cord Injury
by Wise Young PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, NJ 08854-8082
17 December 2008

I write to wish everybody Happy Holidays and to explain why I have so much hope for 2009:

1. A Renaissance of Stem Cell Research. For nearly 8 years, the Bush Administration has suppressed not only embryonic stem cell (ESC) research but all stem cell research.  Last year, for example, NIH funded only $600 million of stem cell research, i.e. $300 million for animal stem cells, $260 million for human adult stem cells, and $40 million for human ESC.  The total NIH budget was about $30 billion i 2007.  So, even though stem cells are widely acknowledged by scientists to be the most important biomedical advance of the decade, the NIH spent only 2% of its budget on all of stem cell research, only 1% on human stem cells, and less than 0.2% on human ESC research.  The Obama Administration will lift these restrictions and strongly encourage stem cell research.  I hope for a renaissance of stem cell research in 2009.
2. The Christopher and Dana Reeve Paralysis Act.  In 2003, Christopher Reeve proposed legislation to encourage research to reverse paralysis.  Now called the Christopher and Dana Reeve Paralysis Act (CDRPA), this bill will fund NIH and other governmental agencies to accelerate development of therapies to reverse paralysis.  In 2005 and each year after Christopher Reeve’s untimely death, members of the spinal cord injury community lobbied in Washington DC for the bill.  In 2006, the House and Senate resurrected the bill.  In October 2007, the House of Representatives passed the bill by a large majority and sent the bill to the Senate.  However, Senator Tom Coburn of Oklahoma singlehandedly stopped the bill and prevented it from coming to a vote.  With a larger Democratic majority in the Senate, CRDPA should pass in 2009.  I sincerely hope that it will bring much needed funding for paralysis research and clinical trials for spinal cord injury.
3. Promising SCI Therapies.  Many therapies improve neurological recovery in animal SCI models.
   • Nogo receptor protein. Biogen recently made a soluble Nogo receptor protein that will bind to all molecules that activate the Nogo receptor.  Animal eperiments suggest that this protein stimulates regeneration after spinal cordinjury. They are thinking of starting clinical trials in China.  I hope so.
   • Chondroitinase. The extracellular matrix of injured spinal cords accumulate a substance called chondroitin-6-sulfate proteoglycan (CSPG) and blocks regeneration.  Chondroitinase is a bacterial enzyme that breaks down CSPG and allows regeneration of axons.  Many laboratories since 2001 have confirmed that chondrotinase facilitates regeneration in the spinal cord of rats.  Acorda Therapeutics licensed this treatment and is developing it.  I hope that it goes into clinical trial.
   • Decorin. This is an extracellular protein that Stephen Davies found to enhance regeneration in the spinal cord.  He is now doing experiments in chronic spinal cord injury.  Decorin is a natural substance that normally “decorates” collagen but is not usually found in the injured spinal cord.  Thus is an interesting and important therapeutic approach to regenerating the spinal cord.  I hope that the experiments in chronic spinal cord injury show positive results.
   • Mesenchymal Stem Cells. These are stem cells present in many tissues, including bone marrow, fat, skin, blood, and gut.  Many laboratories have reported that these mesenchymal stem cells are beneficial in animal models of spinal cord injury, including stimulation of remyelination.  Because these cells would be isolated from the same individuals, they should be immune-compatible.  Many groups are beginning to study such cells for stroke in clinical trial.
   • Induced Pluripotent Stem Cells. Until recently, there were only two source of immune-compatible stem cells for transplantation: umbilical cord blood and bone marrow mesenchymal stem cells.  Now, for the first time, by expressing four genes, scientists can convert skin and other cells to pluripotent stem cells.  Many groups are working feverishly on safe methods to convert these cells without using viruses and with less risk of producing tumors.  I am looking forward to reports of beneficial effects of IPS cell transplants in spinal cord injury.
4. Clinical trials.  Several therapies are already in or should soon be in clinical trial.
   • Nogo antibody.* Nogo is a myelin protein that blocks regeneration. Novartis is now testing Nogo antibodies in patients with chronic spinal cord injury in Europe.  This antibody has shown promise in animal studies. I hope that this trial shows positive results.
   • Cethrin.*  Bioaxone completed a phase 2 clinical trial showing that Cethrin improves neurologic recovery in patients with spinal cord injury.  Cethrin is a modified bacterial toxin that blocks rho, the intracellular messenger for the Nogo receptor.  Alceres recently bought Bioaxone and will start more trials with Cethrin.  I hope that they are successful in raising funds for the trial.
   • Lithium.  In 2004, Yick, et al. at Hong Kong University reported that lithium and chondroitinase stimulate regeneration and improve neurological recovery after spinal cord injury.  Recent studies indicate that lithium stimulates stem cells to proliferate and produce neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), and glia-derived neurotrophic factor (GDNF).  A recent clinical trials suggests that lithium may be beneficial for amyotrophic lateral sclerosis.  ChinaSCINet completed a phase 1 trial showing that lithium can be safely given to people with chronic spinal cord injury and is now doing a phase 2 study comparing a 6-week course of lithium with placebo.  I hope that this trial shows positive results.
   • Umbilical cord blood mononuclear cells (UCBMC). Several independent laboratories have reported beneficial effects of UCBMC on animal SCI models.  Several clinics have been using the cells.  The China Spinal Cord Injury Network is applying for permission to carry out the first clinical trial of this treatment in chronic spinal cord injury.
   • Embryonic stem cells (ESC). Hans Keirstead at UC Irvine has reported that human ESC-derived oligodendroglial precursor cells improve regeneration and locomotor recovery in rats.  Regeneron has applied for permission to test these cells in patients with subacute spinal cord injury.  The trial is likely to be approved in 2009 and will be the first clinical trial of human ESC.
   • Schwann cell transplants. Much animal data suggest beneficial effects of Schwann cell transplants in spinal cord injury, particularly in combination with drugs that increase cAMP levels in the spinal cord.  After being discussed for many years, the first clinical trials of Schwann cell transplants for spinal cord injury may start in the United States.  Several groups in China have transplanted fetal and adult Schwann cells to people with subacute and chronic spinal cord injury.  The Miami Project is planning clinical trials to assess autografts of Schwann cells.  I hope that these trials start in 2009.
5. Clinical Trial Networks.  Clinical trial networks are being established for spinal cord injury around the world.
   • The China Spinal Cord Injury Network (ChinaSCINet).  This is a network of 24 major spinal cord injury centers in mainland China, Hong Kong, and Taiwan.  This is the network that I have spent four years building in China.  We completed an observation trial of over 500 subjects, a phase 1 study to assess safety and feasibility of giving a 6-week course of lithium to people with chronic SCI, and started a phase 2 trial to compare lithium versus placebo treatment of chronic SCI.  We have applied for a phase 2 to assess increasing doses of umbilical cord blood mononuclear cell (UCBM) transplants and a phase 3 trial to assess UCBM cells with and without lithium.
   • A U.S. Spinal Cord Injury Network. We are planning and raising money for this network to do parallel clinical trials of cord blood mononuclear cell transplants and lithium transplants in chronic spinal cord injury.  Several centers have signed up for this study in New Jersey, Philadelophia, New York, and Austin (TX).  During 2009, we will be training and fundraising.  We hope to start trials in 2010.
   • North American Spinal Cord Injury Network. Funded in part by Reeve Foundation, this network has already started an observational trial.  It is planning trials of acute spinal cord injury therapies in conjunction with other networks.
   • Rehabilitation Networks. In France, a network of 148 rehabilitation units that treat SCI have begun to work together.  In the United States, the Spinal Cord Injury Locomotor Trial (SCILT) evaluated walking outcomes.

In summary, there is much reason for hope for spinal cord injury research.  The year 2009 should be a renaissance of stem cell research. Hopefully, Congress will pass the Christopher and Dana Reeve Paralysis Act, which many of us have lobbied for, to provide much needed funding for paralysis research and clinical trials.  Many promising therapies have been shown to improve recovery in animals and are ready for clinical trials.  Several clinical trial networks have been or are being formed to test these therapies.  I believe that much of this hard work will come to fruition in 2009.  Merry Christmas and Happy New Year!

Wise.

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