Neuroscience Graduate Program at UCSF
Inherited and Environmentally Induced Retinal Degenerations
The focus of our laboratory is photoreceptor degeneration, the cause of blinding diseases such as retinitis pigmentosa, which affects approximately 1:3,500 people worldwide, and age-related macular degeneration, which affects vision in the elderly in as many as 1:3 by the age of 75. Virtually no widely accepted forms of therapy exist for these diseases. We have been involved in several lines of research aimed at modulating the rate of photoreceptor degeneration by both genetic and environmental means; to develop mutant rhodopsin transgenic rat models with which to study various forms of therapy; to study the efficacy of neurotrophic factors in slowing the progression of degeneration; to understand the cellular and molecular mechanisms of injury-induced protection; to develop gene-based delivery of neurotrophic factors; and to develop gene-based ribozyme therapy for the treatment of dominantly inherited disorders. Much of our current research stems from our original observation that bFGF can slow photoreceptor degeneration in RCS rats with inherited retinal dystrophy, the first such pharmaceutical effect in retinal degenerations, and that various growth factors, neurotrophins and cytokines, can protect photoreceptors from cell death due to excessive light.
Ongoing projects include:
1. Modulation of photoreceptor degeneration by genetic and environmental means.
2. Development of transgenic rats with mutant rhodopsin genes.
3. Efficacy and mechanisms of neurotrophic factor slowing of photoreceptor degenerations.
4. Gene-based delivery of neurotrophic factors to degenerating retinas.5. Ribozyme therapy for dominantly inherited retinal degenerations.
M.D., China M.A., Univ. of Houston
AAV-mediated neurotrophic factor delivery
Mentored Clinical Scientist Development Awardee
B.S., Stanford M.D., UCSF
AAV-mediated ribozyme therapy
Faktorovich, E. G., Steinberg, R. H., Yasumura, D., Matthes, M. T., and LaVail, M. M. (1990) Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 347: 83-86.
LaVail, M. M., Unoki, K., Yasumura, D., Matthes, M. T., Yancopoulos, G. D., and Steinberg, R. H. (1992) Multiple growth factors, cytokines and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc. Natl. Acad. Sci. USA 89: 11249-11253.
Faktorovich, E. G., Steinberg, R. H., Yasumura, D., Matthes, M. T., and LaVail, M. M. (1992) Basic fibroblast growth factor and local injury protect photoreceptors from light damage in the rat. J. Neurosci. 12: 3554-3567.
Lewin, A. S., Drenser, K. A., Hauswirth, W. W., Nishikawa, S., Yasumura, D., Flannery, J. G., and LaVail, M. M. (1998) Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nature Med. 4: 967-971.
D'Cruz, P. M., Yasumura, D., Weir, J., Matthes, M., Abderrahim, H., LaVail, M. M., and Vollrath, D. (2000) Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum. Mol. Genet. 9: 645-651.Danciger, M., Matthes, M. T., Yasumura, D., Akhmedov, N. B., Rickabaugh, T., Gentleman, S., Redmond, T. M., LaVail, M. M., and Farber, D. B. (2000) A QTL on distal chromosome 3 that influences the severity of light-induced damage to mouse photoreceptors. Mamm. Genome 11: 422-427.