The most common inherited human disorder causing blindness is retinitis pigmentosa (RP), and the most common cause of blindness in persons over the age of 60 is age-related macular degeneration (AMD). Blindness in both of these families of diseases is caused by photoreceptor cell death. At present, no widely accepted form of therapy exists for these diseases. Three experimental therapeutic approaches are proposed to prevent photoreceptor cell death in animal models, principally transgenic rats with two different types of rhodopsin gene mutations. These three approaches are the direct intraocular injection of neurotrophic factors, the delivery of neurotrophic factors to the photoreceptors by gene transfer using recombinant adeno-associated viral vectors, and the delivery by gene transfer to photoreceptors of ribozymes, small catalytic RNA molecules that can reduce the production of harmful mutant proteins produced by dominant gene mutations. Each of these three approaches has been shown, at least in initial studies, to reduce the rate of photoreceptor degeneration in the transgenic rats or in other models of retinal degeneration. This proposal aims at clarifying many of the key questions that relate to the new experimental therapeutic approaches, including how long can photoreceptor degeneration be slowed by a single application of an agent or therapeutic approach; does multiple application or sustained delivery have a greater protective effect than a single application of a protective agent; at which stage(s) of the degeneration are the approaches effective ; are the approaches mutation-specific; are combinations of neurotrophic factors more effective than single agents; are combinations of therapeutic approaches more effective than single approaches; is functional rescue, which has been seen by electroretinography, a preservation of function or a recovery of function; what is the relationship between rod and cone photoreceptor cell function and cell death; and can cone photoreceptors be protected specifically by the therapeutic approaches? The primary research methods to be used with transgenic mice and rats with inherited retinal degeneration are quantitative anatomical techniques, electroretinography, gene transfer technology and the polymerase chain reaction to identify genotypes. It is anticipated that the results obtained in this study will be highly relevant to the design and implementation of therapeutic trials with human patients with retinitis pigmentosa, one of which is already in the planning stage.
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