Matthew LaVail, PhD, Professor
matthew.lavail@ucsf.edu
Administrative Assistant: 415-476-2433

Cellular Mechanisms of Retinal Degeneration

Our laboratory is concerned primarily with the causes of photoreceptor degeneration and the means to protect photoreceptors from dying and thereby prevent or delay the onset of blindness. We study rodent models of photoreceptor degenerations like those that occur in the human diseases, retinitis pigmentosa and macular degeneration, as well as the damaging effects of environmental light on the retina as an experimental model of retinal degeneration. The specific causes of photoreceptor cell death are obscure in most forms of retinal degeneration and, heretofore, there has been no clearly effective treatment or cure for these diseases.

Our current research is aimed at developing a medical therapy for these diseases. The effort stems from our initial observation that the peptide, basic fibroblast growth factor (bFGF), when injected into the eye dramatically reduces the rate of photoreceptor degeneration in an inherited retinal degeneration in the rat and in light damage to the normal albino rat. Most remarkably, we have found significant survival-promoting activity with several additional growth factors, cytokines and neurotrophins, known collectively as “survival factors.” Some of these appear to be even more potent than bFGF and may have fewer potentially harmful side effects. We have continued this work by demonstrating that survival factors can protect the retina from degeneration in three forms of retinal degeneration in the mouse and in several lines of newly developed transgenic rats. These rats have genetic defects similar to those in human patients with mutations in the rhodopsin gene that produce an autosomal dominant form of retinitis pigmentosa.

Recently, we have used the electroretinogram (ERG), a non-invasive electrical measure of retinal function, to assess the protective effect of injected survival factors on retinal function. We now have shown much greater functional activity in the factor-injected eyes than in the control eyes. Thus, we now have demonstrated not only structural but also functional protection by survival factors.

One of the hurdles that must be overcome for survival factors to be used effectively in the human eye is the method of delivery. Because the agents cannot enter the eye via a systemic injection, they presently must be injected directly into the eye. We are exploring two ways to circumvent this problem. First, we are involved in collaborative research to develop a method for sustained release of the agents in the eye. Second, we are using a form of gene therapy, developing molecular biological methods to insert genes that will cause cells within the eye to provide survival factors to photoreceptors continuously. In sum, our studies offer the possibility of developing pharmacological therapy for some forms of retinal degeneration that may slow down their progress or prevent them altogether.

Complete list of Publications/PubMed

Selected Publications

LaVail, M.M., Yasumura, D., Matthes, M.T., Lau-Villacorta, C., Unoki, K., Sung, C.-H. and Steinberg, R.H.: Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest. Ophthal. Vis. Sci. 39:592-602, 1998.

D'Cruz, P.M., Yasumura, D., Weir, J., Matthes, M., Abderrahim, H., LaVail, M.M. and Vollrath, D.: Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum. Mol. Genet. 9:645-651, 2000.

Danciger, M., Matthes, M.T., Yasumura, D., Akhmedov, N.B., Rickabaugh, T., Gentleman, S., Redmond, T.M., LaVail, M.M. and Farber, D.B.: A QTL on distal chromosome 3 that influences the severity of light-induced damage to mouse photoreceptors. Mamm. Genome 11:422-427, 2000.

LaVail, M.M., Yasumura, D., Matthes, M.T., Drenser, K.A., Flannery, J.G., Lewin, A.S. and Hauswirth, W.W.: Ribozyme rescue of photoreceptor cells in P23H transgenic rats: long-term survival and late-stage therapy. Proc. Natl. Acad. Sci., USA. 97:11488-11493, 2000.

Vollrath, D., Feng, W., Duncan, J.L., Yasumura, D., D'Cruz, P.M., Chappelow, A., Matthes, M.T., Kay, M.A. and LaVail, M.M.: Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc. Natl. Acad. Sci., USA. (In press) 2001.