The goal of this project is to develop a novel therapeutic application that utilizes a protein unfolding ATPase
for the treatment of inherited retinal dystrophies, including retinitis pigmentosa. This strategy is based on the
premise that many of these genetically diverse hereditary diseases, which are characterized by the slow
impending death of photoreceptor neurons, nevertheless, share a common etiology from the cytotoxicity of
proteins misfolded as a result of mutations. To counteract this toxicity, we have genetically introduced a
protein-unfolding ATPase from Archaea into the retinal rod photoreceptors of mice for the purpose of purging
misfolded proteins. To test our hypothesis and attain our proposed research goals, the following three Specific
Aims have been identified in this proposal. In Specific Aim 1 we will investigate the mechanism whereby the
archaeal chaperone protects mouse photoreceptors from cytotoxic misfolded proteins. Specific Aim 2 of the
proposed studies will ascertain the effectiveness of this intervention to avert the progression of retinal
degeneration in two established RP mouse models. The focus of Specific Aim 3 is testing the therapeutic
potential of a viral vector that enables the delivery of the protein unfolding ATPase into photoreceptor cells.
These studies, to be conducted in mice, will be part of the first step toward developing a similar therapeutic
application against retinitis pigmentosa in human patients.