Regeneration Therapies
Please note: these are draft pages we put them together
so we could collaborate more efficiently and we do invite
suggestions from researchers.
1. Sub-Category Index
2. Introduction
3. Analysis
4. Projections
5. Human Trials Update
6. Projected Research Funding FY 1996
6.5 A list of what will not be funded
7. Key Researchers in this Field
1. Sub-Category Index
a. IN-1, the monoclonal antibody against neurite inhibitor factor (NIF) from Schwab
b. NT3 - neurotrophic growth factor
c. Anti-Mag - antibodies against myelin-associated glycoprotein
d. L1 - a cellular adhesion molecule
e. many others that have not yet tried in spinal cord injury models.
g. Scar Disrupters combined w/NGF
2. Regeneration: Introduction
by Dr. Wise Young, January 18,1996
Regeneration of the spinal cord has been the holy grail of neuroscientists for many years. At the turn of the century, the famous Spanish neuroanatomist Santiago Ramon y Cajal convinced the world the brain and spinal cord are composed on specialized cells called neurons that contacted and communicated with each other through long processes called axons.
The spinal cord is composed of long tracts of axons that connect neurons in the brain and neurons in the spinal cord. Axons are covered with a white sheathing called myelin. Cajal noted that when he cut the spinal cord, the distal part of the axon would die while the proximal part tended to die back a short distance. Some of the axons tried to regrow but only for short distances and would stop. Based on these observations, most scientists concluded that the brain and spinal cord neurons cannot regenerate. However, axons in peripheral nerve will grow back if cut.
In the early 1980's, Albert Aguayo at the Montreal Institute of Neurology in Canada came to a different conclusion. He stuck peripheral nerves into the spinal cord and found that brain and spinal neurons will send axons into the peripheral nerves and these axons grew long distances. He suggested that there was something in brain that inhibited axonal growth. This stimulated an intense search for inhibitory substances in the spinal cord.
In 1987, the Swiss researcher Martin Schwab showed that myelin (the sheathing that covers axons in the central nervous system) contains a protein that blocks regeneration. He showed that axons will be grow in the presence of this protein. He subsequently developed an antibody to block the protein and found that this antibody allowed regeneration in the spinal cord. Reported in 1991, this was the first time a treatment was able to stimulate regeneration in the spinal cord. This discovery has led to an intense search for other potentially inhibiting factors. Several others have been reported, i.e. myelin-associated glycoprotein (MAG) and others.
In the meantime, other researchers, particularly the Hans Thoenen and Yves-Alain Barde in Germany, discovered that the brain and spinal cord produce growth factors that stimulated nerve growth. A family of these growth factors, called neurotrophins, have now been identified. One of these factors, NT-3, appeared to be particularly effective stimulating growth of spinal axons. In 1993, Schwab showed that a combination of the antibody (called IN-1) and a neurotrophic factor (called NT3) was better than either alone. In December 1996, Schwab published an important paper with Barbara Bregman, showing that IN1-NT3 treatment resulted in functional recovery.
Several laboratories have begun reporting that cellular adhesion molecules (CAM) play a major role in axonal growth. CAMs are molecules that are present on membrane surfaces and have long been believed to guide growing axons. However, Melitta Schachner in Switzerland showed that one CAM called L1 not only strongly stimulated axonal growth but appeared to do so despite the presence of the inhibiting glycoprotein described by Schwab.
Schachner proposed that L1 is the natural antagonist to growth inhibiting proteins of the central nervous system. Several observations strongly supported this proposal. First, wherever L1 is present, axonal growth occurs. For example, during embryonic development, when the spinal cord grew. Also, peripheral nerves express L1 and can regenerate. Second, L1 is absent in tissues that cannot regenerate. For example, L1 is largely absent from white matter in adult spinal cords. Third, when she genetically manipulated mouse to express L1 in the adult central nervous system. Seveal laboratories, including NYU, are actively pursuing this lead.
A large number of growth factors have been reported to stimulate neuronal growth, including fibroblast growth factor (FGF), brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), insulin-like growth factor (IGF), and others. None of these, however, have yet to be tested in standardized animal spinal cord injury models. Many other substances show promise in tissue culture studies have have not yet been tested in vivo. Finally, many laboratories have been studying implantation of fetal cells into the spinal cord but the political ramifications of human fetal cell transplants may interfere.
In summary, recent advances indicate that regeneration can occur in the spinal cord under the right circumstances. It is likely that the treatment will include not only a growth factor but a factor that antagonizes endogenous growth inhibitors in central nervous tissues. Animal studies are progressing and there is no dearth of factors and substances to test in the laboratory.
5. Human Trials
Depending on what the animal studies show, the first regenerative therapies for spinal cord injury are probably either IN1 or possibly L1, combined with NT3. IN1+NT3 is the only treatment has has so far been shown to result in functional recovery associated with regeneration in mammalian spinal cord. There are many issues to be settled, including the delivery vehicle, whether we would use genetically modified cells that secrete these factors or whether we would deliver the drug directly to the spinal cord through intrathecal catheters. Given the current state of funding and progress, perhaps the first regenerative therapies will go into clinical trial 4-8 years from now.
Background Treatments that regenerate the spinal cord include IN1 (the antibody that blocks inhibitory proteins in the spinal cord) and NT3 (neurotrophin-3, the growth factor shown to stimulate spinal axonal growth in rats). Swiss researcher Dr. Martin Schwab showed in 1987 that spinal white matter contains a protein that stops regeneration. Blockade of this protein with a monoclonal antibody resulted in the first demonstration of regeneration in mammals by 1991. In 1993, Schwab showed that a combination of the antibody (called IN-1) and a neurotrophic factor (called NT3) was better than either alone.
In January of 1996, Schwab published an important paper with Barbara Bregman, showing that IN1-NT3 treatment resulted in functional recovery. This discovery has led to an intense search for other potentially inhibiting factors. Several others have been reported, i.e. myelin-associated glycoprotein (MAG) and others.
In the meantime, several laboratories have begun reporting that cellular adhesion molecules (CAM) play a major role and are likely to be the natural antagonists to the growth inhibiting proteins of the central nervous system. In particular, Melitta Schachner has shown that a CAM by the name of L1 strongly stimulates regeneration in the central nervous system and L1 studies are now being carried out in spinal cord injury models in a number of laboratories, including NYU, Miami Project, UCSD, Case Western, and others.
Depending on what the animal studies show, we are hoping to start therapy with IN1 or L1, combined with NT3, sometime in 1998. We are still uncertain of the delivery vehicle, whether we would use genetically modified cells that secrete these factors or whether we would deliver the drug directly to the spinal cord through intrathecal catheters.
6. Funding Issues
Martin's antibody patent has been assigned to a company called Regeneron. Although Martin is working very hard on isolating the glycoprotein that is responsible for inhibiting regeneration, he has not yet been successful.
He has gone on to show that treatment with IN1 and NT3 combined does result in better restoration of locomotor function. After nearly a year of wrangling, his paper reporting this was accepted by Nature and will be published next month.
Unfortunately, Regeneron has indicated to me that they are not interested in and have no plans to invest in spinal cord injury therapies. They believe that the field is too small and risky to warrant the investment. I am hoping to convince Regeneron to license the treatment to us so that we can take it to clinical trial. The problem is money. No major pharmaceutical company is interested in investing the $50-$200 million necessary to take a treatment from laboratory to market, for spinal cord injury.