AUTHOR=Jiang Li , Frederick Jeanne M., Baehr Wolfgang 

TITLE=RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 7 - 2014

YEAR=2014

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2014.00025

DOI=10.3389/fnmol.2014.00025

ISSN=1662-5099

ABSTRACT=RNA interference (RNAi) knockdown is an efficacious therapeutic strategy for silencing genes causative for dominant retinal dystrophies. To test this, we used self-complementary (sc) AAV2/8 vector to develop an RNAi-based therapy in two dominant retinal degeneration mouse models. The allele-specific model expresses transgenic bovine GCAP1(Y99C) establishing a rapid RP-like phenotype, whereas the nonallele-specific model expresses mouse GCAP1(L151F) producing a slowly progressing cone/rod dystrophy (CORD). The late onset GCAP1(L151F)-CORD mimics the dystrophy observed in human GCAP1-CORD patients. Subretinal injection of scAAV2/8 carrying shRNA expression cassettes specific for bovine or mouse GCAP1 showed strong expression at one week post-injection.  In both allele-specific (GCAP1(Y99C)-RP) and nonallele-specific (GCAP1(L151F)-CORD) models of dominant retinal dystrophy, RNAi-mediated gene silencing enhanced photoreceptor survival, delayed onset of degeneration and improved visual function. Such results provide a “proof of concept” toward effective RNAi-based gene therapy mediated by scAAV2/8 for dominant retinal disease based on GCAP1 mutation. Further, nonallele-specific RNAi knockdown of GCAP1 may prove generally applicable toward the rescue of any human GCAP1-based dominant cone-rod dystrophy.