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

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Publication Type pre-print
School or College School of Medicine
Department Ophthalmology
Creator Frederick, Jeanne M.
Other Author Jiang, Li.; Baehr, Wolfgang
Title RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations
Date 2014-01-01
Description RNA interference (RNAi) knockdown is an efficacious therapeutic strategy for silencing genes causative for dominant retinal dystrophies. To test this, we used self-complementry (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 expressed mouse GCAP1(L151F) producing a slowly progressing cone-rod dystrophy (CORD). The late onset GCAP1(151F)-CORD mimics the dystrophy observed in human GCAP1-CORD patients. Subretinal injection of scAAV2/8 carrying shRNA expression cassettes specific for bovine or mouse guanylate cyclase-activating protein 1 (GCAP1) showed strong expression at 1 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 GCAPi mutation. Further, nonallele-specific RNAi knockdown of GCApi may prove generally applicable toward the rescue of any human GCApi-based dominant cone-rod dystrophy.
Type Text
Publisher Frontiers Media
Volume 7
Issue 1
First Page 1
Last Page 8
Language eng
Bibliographic Citation Jiang, L., Frederick, J. M., & Baehr, W. (2014). RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations. Frontiers in Molecular Neuroscience, 7(1 APR), 1-8.
Format Medium application/pdf
Format Extent 2,229,442 bytes
Identifier uspace,18646
ARK ark:/87278/s6hb2f9s
Setname ir_uspace
Date Created 2014-05-12
Date Modified 2021-05-06
ID 712535
Reference URL https://collections.lib.utah.edu/ark:/87278/s6hb2f9s
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