Long-term RNA interference gene therapy in a dominant retinitis pigmentosa mouse model

被引：39

作者：

Jiang, Li ^{[1
]}

Zhang, Houbin ^{[1
]}

Dizhoor, Alexander M. ^{[3
,4
]}

Boye, Shannon E. ^{[5
]}

Hauswirth, William W. ^{[5
]}

Frederick, Jeanne M. ^{[1
]}

Baehr, Wolfgang ^{[1
,2
,6
]}

机构：

[1] Univ Utah, Hlth Sci Ctr, Dept Ophthalmol & Visual Sci, Salt Lake City, UT 84132 USA

[2] Univ Utah, Hlth Sci Ctr, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA

[3] Salus Univ, Dept Basic Sci, Elkins Pk, PA 19027 USA

[4] Salus Univ, Penn Coll Optometry, Elkins Pk, PA 19027 USA

[5] Univ Florida, Coll Med, Dept Ophthalmol, Gainesville, FL 32610 USA

[6] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 45期

基金：

美国国家卫生研究院;

关键词：

human retina disease; transgenic mouse model; short hairpin RNA knockdown; rod and cone photoreceptors; CYCLASE-ACTIVATING PROTEIN-1; CONE-ROD DYSTROPHY; GUANYLATE-CYCLASE; PHOTORECEPTOR DEGENERATION; OCULAR NEOVASCULARIZATION; KNOCKOUT MICE; MUTATION; SIRNA; SUPPRESSION; GUCA1A;

D O I：

10.1073/pnas.1112758108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

RNA interference (RNAi) gene silencing is a potential therapeutic strategy for dominant retinal degeneration disorders. We used self-complementary (sc) AAV2/8 vector to develop an RNAi-based gene therapy in a dominant retinal degeneration mouse model expressing bovine GCAP1(Y99C). We established an in vitro shRNA screening assay based on EGFP-tagged bovine GCAP1, and identified a shRNA that effectively silenced the bovine GCAP1 transgene with similar to 80% efficiency. Subretinal injection of scAAV2/8 carrying shRNA expression cassette showed robust expression as early as 1 wk after injection. The gene silencing significantly improved photoreceptor survival, delayed disease onset, and increased visual function. Our results provide a promising strategy toward effective RNAi-based gene therapy by scAAV2/8 delivery for dominant retinal diseases.

引用

页码：18476 / 18481

页数：6

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