AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

被引：49

作者：

Boye, Sanford L. ^{[1
]}

Peshenko, Igor V. ^{[2
,3
]}

Huang, Wei Chieh ^{[4
]}

Min, Seok Hong ^{[1
]}

McDoom, Issam ^{[1
]}

Kay, Christine N. ^{[1
]}

Liu, Xuan ^{[1
]}

Dyka, Frank M. ^{[1
]}

Foster, Thomas C. ^{[5
]}

Umino, Yumiko ^{[6
]}

Karan, Sukanya ^{[7
]}

Jacobson, Samuel G. ^{[4
]}

Baehr, Wolfgang ^{[7
]}

Dizhoor, Alexander ^{[2
,3
]}

Hauswirth, William W. ^{[1
]}

Boye, Shannon E. ^{[1
]}

机构：

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

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

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

[4] Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA

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

[6] SUNY Upstate Med Univ, Coll Med, Dept Ophthalmol, Syracuse, NY 13210 USA

[7] Univ Utah, Hlth Sci Ctr, John A Moran Eye Ctr, Dept Ophthalmol, Salt Lake City, UT 84112 USA

来源：

HUMAN GENE THERAPY | 2013年 / 24卷 / 02期

关键词：

LONG-TERM PRESERVATION; VISUAL FUNCTION; PHOTORECEPTOR DEGENERATION; RETINAL DEGENERATION; RPE65; MUTATIONS; CONE FUNCTION; ROD; RESTORATION; VISION; EXPRESSION;

D O I：

10.1089/hum.2012.193

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1). GUCY2D encodes photoreceptor-specific, retinal guanylate cyclase-1 (RetGC1). Reports of retinal degeneration in LCA1 are conflicting; some describe no obvious degeneration and others report loss of both rods and cones. Proof of concept studies in models representing the spectrum of phenotypes is warranted. We have previously demonstrated adeno-associated virus (AAV)-mediated RetGC1 is therapeutic in GC1ko mice, a model exhibiting loss of cones only. The purpose of this study was to characterize AAV-mediated gene therapy in the RetGC1/RetGC2 double knockout (GCdko) mouse, a model lacking rod and cone function and exhibiting progressive loss of both photoreceptor subclasses. Use of this model also allowed for the evaluation of the functional efficiency of transgenic RetGC1 isozyme. Subretinal delivery of AAV8(Y733F) vector containing the human rhodopsin kinase (hGRK1) promoter driving murine Gucy2e was performed in GCdko mice at various postnatal time points. Treatment resulted in restoration of rod and cone function at all treatment ages and preservation of retinal structure in GCdko mice treated as late as 7 weeks of age. Functional gains and structural preservation were stable for at least 1 year. Treatment also conferred cortical-and subcortical-based visually-guided behavior. Functional efficiency of transgenic RetGC1 was indistinguishable from that of endogenous isozyme in congenic wild-type (WT) mice. This study clearly demonstrates AAV-mediated RetGC1 expression restores function to and preserves structure of rod and cone photoreceptors in a degenerative model of retinal guanylate cyclase deficiency, further supporting development of an AAV-based vector for treatment of LCA1.

引用

页码：189 / 202

页数：14

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