The pathogenesis of visual loss in retinal degenerations is complex. Our understanding of some of the early molecular and cellular events involved in the process has increased greatly, but all the mechanistic details and ways to halt or reverse the blindness are still not known. Recently, a hypothesis was advanced to explain part of the visual loss in a hereditary retinal disease, which has been considered one of the genetic models of AMD, the most common form of blindness in older adults. The hypothesis was tested pharmacologically by administering a nutrient to patients with the genetic disease and the result was a dramatic improvement in their vision. The present proposal is to extend this preliminary work to a larger number of patients with the hereditary retinal disease and to other patients who may share this pathogenesis of visual loss. The impetus for the preliminary studies leading to this proposal was the recent discovery that the autosomal dominant retinal degeneration, SFD, was caused by mutations in the gene encoding an extracellular matrix molecule known as tissue inhibitor of metalloproteinases-3 (TIMP-3). This discovery, together with earlier clinical and histopathological observations, prompted the hypothesis that the extracellular matrix abnormality in SFD could lead to defective vision by disturbing the visual (retinoid) cycle and causing a vitamin A deficiency-like dysfunction in the photoreceptors. The hypothesis was tested in SFD patients with a codon 167 TIMP-3 gene mutation by administering to them high doses of vitamin A orally for one month. Within a few days, there was dramatic restoration of rod photoreceptor function in patients with early disease; in more advanced cases, increases in rod and cone function around macular scars occurred after a month. Non-invasive techniques yielding results that can be interpreted in terms of physiological and biochemical processes will be used to explore further the mechanisms of visual loss and the response to pharmacologic intervention with vitamin A in a larger number of SFD patients with different TIMP-3 genotypes and in two other groups of patients who show the same visual cycle disturbance as SFD. The other groups include a subset of patients with AMD and late-onset forms of RP. The results of this research will lead to the formulation of hypotheses about the underlying molecular events in these diseases and may evolve into recommendations for treatment paradigms in these blinding retinal degenerations.
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