Abstract
Abstract: :
Purpose: Retinal diseases associated with mutations in the photoreceptor–specific protein, peripherin/rds (P/rds) vary widely in effect and severity. Herein, we tested a strategy for obtaining significant functional and structural rescue of animal models carrying point mutations in P/rds. Methods: Two transgenic mouse models were generated and characterized, carrying either the C214S or R172W mutation in P/rds, which cause rod– and cone–dominant defects, respectively. A third model over–expressing normal mouse P/rds (NMP) was used to generate double transgenics (C214S/NMP and R172W/NMP) on an rds+/– genetic background, to achieve uniform P/rds supplementation to both rods and cones in the mutant models. Electroretinography, histology at the light and electron microscopy levels, immuno–gold cytochemistry (using anti–rod and –cone opsin antibodies), Western blot analysis, and limited tryptic digestion were used to assess rescue of the retinal disease phenotypes. Results: Defects in rod function and outer segment (OS) structure were markedly ameliorated in the C214S (loss–of–function) model by supplementation with normal P/rds, up to 7 mo. of age. P/rds supplementation in the R172W (gain–of–function) model enhanced the stability of P/rds complex formation, improved cone function, and restored cone OS integrity, up to 3 mo. of age. Conclusions: Genetic supplementation with normal P/rds can rescue P/rds–induced retinal disease. This study provides the first evidence for P/rds supplementation–mediated rescue of both rod and cone–dominant disease–causing mutations. This strategy may have broader implications for clinical intervention in P/rds–associated retinal diseases.
Keywords: gene transfer/gene therapy • retinal degenerations: hereditary • photoreceptors: visual performance