Using Nanotechnology to Rescue Visual Loss in A Model of Human Blinding Disorder

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DESCRIPTION (provided by applicant): Macular degeneration (MD) is a group of inherited retinal diseases characterized by the death of cone photoreceptor cells in the macular region of the retina. Among the genes in which mutations have been identified in patients with MD, peripherin/rds (P/rds) is the one with a large number of mutations. To date, more than thirty different mutations in the P/rds gene have been identified to associate with MD and the R172W mutation is the most common one identified in MD patients. We have established a transgenic mouse model of cone-dominant degeneration in which mice express R172W P/rds in both rods and cones. The phenotype of the mice resembles the symptoms in patients carrying the same mutation and functional, structural and biochemical analyses showed a direct correlation between transgene expression levels and the onset/severity of the cone degeneration in these mice. There are currently no clinically acceptable treatments available for MD and cone-rod dystrophy. As the first mouse model of cone-dominant degeneration associated with P/rds mutation, the R172W mice provide a valuable tool to study the treatment of cone degenerative diseases. Recent pre-clinical and clinical trials have shown promise of gene replacement therapy in the inherited gene-deficient diseases. The compacted DNA nanoparticle delivery, as a novel, non-viral approach, has been shown to mediate efficient therapeutic gene transfer and expression. This proposal is aimed to explore the therapeutical potential of DNA nanoparticles to improve the natural history of P/rds-associated MD and cone-rod dystrophy, using R172W mouse model. First, we will evaluate the photoreceptor expression of P/rds transgene in the wild-type mice following subretinal delivery of the DNA nanoparticles. The toxicity and inflammatory responses following the subretinal injection will be evaluated for both morphological and biochemical perspectives. Secondly, we will assess the rescue of the cone-dominant degeneration in R172W mice by the nanoparticle gene delivery. We hypothesize that the degenerative phenotype in R172W mice will be rescued or partially rescued by replacement delivery of the P/rds nanoparticles. Information obtained from the proposed study will open a new pathway for therapeutic interventions of retinal degeneration and will have significant impact on the clinical treatment of human retinal diseases.