Therapeutic intervention in mouse models of retinal degeneration.

摘要

Blindness due to genetic abnormalities in photoreceptor-specific proteins represents a significant health problem worldwide. Over 80 mutations in the photoreceptor-specific protein peripherin/rds (P/ rds) have been associated with human hereditary diseases involving either rod- or cone-dominant retinal degeneration. Gene therapy-directed approaches for the treatment of P/rds-associated retinal disease have been hindered by a haploinsufficiency phenotype, which requires well-regulated expression of P/rds protein levels. A transgenic mouse model expressing wildtype P/rds was used to evaluate the critical level of P/rds needed to maintain photoreceptor structure and function, and to assess the structural and functional consequences of P/rds over-expression. Additionally, transgenic mice carrying point mutations in P/rds (C214S and R172W) which model human rod- and cone disease were characterized functionally and structurally. These transgenics were also used to test the hypothesis that P/ rds supplementation can rescue both rod and cone retinal degenerative phenotypes associated with mutations in P/rds. The biochemical, structural and functional findings of this study provide compelling evidence for P/rds supplementation as an effective, widely applicable strategy for therapeutic intervention in P/rds associated-retinal diseases.