October 17, 2006
Annual Neuroscience Meeting: Trophic Factors a Basis of Therapeutic Approach for ALS[Quick Summary: New research results reported at the Society for Neuroscience Meeting in Atlanta, Ga., show how the cell helpers called trophic factors might serve as the basis for therapeutic approaches in ALS.]
Gene therapies or direct delivery of helper molecules called trophic factors are strategies scientists are investigating for ALS. Advances along these therapeutic avenues as well as the basis of trophic factor involvement in the disease were an important aspect of several sessions at the meeting of the Society for Neuroscience, October 14-18 in Atlanta. At a press conference October 17, Peter Carmeliet, M.D., Ph.D., said that a trial in ALS patients to deliver a trophic factor could start within the next year. A Stockholm based company, NeuroNova, is collaborating to bring the approach to clinical application.
In efforts directed at gene therapies to deliver trophic factors, Christine Haenggeli, M.D., working at Johns Hopkins University with Jeffrey Rothstein, M.D., Ph.D., injected viral vectors directly into the tissue of the spinal cord in mice. Vector delivery of insulin like growth factor 1 (IGF-1) produced a modest increase in survival of about ten days as well as a delay in decline of grip strength.
Brian Kaspar, Ph.D., of the Columbus Children’s Research Institute and collaborators at the biotech company, Genzyme, are also working with IGF-1. Using disarmed virus as a delivery truck for the IGF-1 gene, they placed the therapeutic directly into a brain region, the deep cerebellar nuclei, in mice that have a mutation that produces some inherited forms of ALS. Delivery to this brain region allowed wide distribution of the gene for the trophic factor and produced better survival of motor neurons as well as improved motor performance in the mice.
The focus on trophic factors as therapeutic avenues in ALS was part of a featured lecture on October 16 by Carmeliet on how the blood vessel promoting molecule, vascular endothelial growth factor (VEGF) also serves as a guide for growing nerve fibers. VEGF in fact appears to play an important role in the nervous system as it develops as well as when it ages or develops damage.
Carmeliet and colleagues have shown that lack of VEGF can produce symptoms similar to ALS in mice. Increasing the number of docking sites for VEGF inside motor neurons prolongs survival of mice with the mutation to copper-zinc superoxide dismutase. SOD1 mutant rats survive longer if given a gene therapy delivering the VEGF gene, or if they are given the growth factor itself directly into the chambers of the brain.
Diether Lambrechts, Ph.D., who is working with Carmeliet at the Flanders Interuniversity Institute for Biotechnology in Belgium, presented in a platform session that morning evidence that treatments which inhibit VEGF can accelerate appearance of the disease—the treated SOD1 mice show symptoms earlier than untreated littermates. In this work, funded in part by The ALS Association, the treated mice had ten percent fewer blood vessels.
Another finding on VEGF presented by Lieve Moons, Ph.D., working with Carmeliet, is that the trophic factor increases the branching of nerve endings that are growing towards their targets as young mice develop their nerve-muscle connections.
Other trophic factors are under investigation for applications to ALS. The German biotech company Axaron presented evidence that the trophic factor, granulocyte colony stimulating factor (G-CSF) can increase the number of surviving motor neurons in SOD1 mutant mice. The surviving motor neurons are larger, as are the muscle fibers. This preservation of the nerve-muscle junction would explain the improved motor performance in SOD1 mice treated with G-CSF which the company had reported last year at the Neuroscience meeting.
The ALS Association continues to fund further research into the promise of trophic factors as a therapeutic approach in ALS. Please see the research web pages for further information about the roles of trophic factors in ALS.
