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Journal article
AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis
Human gene therapy, v 24(2), pp 189-202
01 Feb 2013
PMID: 23210611
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis
- Creators
- Sanford L. Boye - University of FloridaIgor V. Peshenko - Salus UniversityWei Chieh Huang - Penn Presbyterian Medical CenterSeok Hong Min - University of FloridaIssam McDoom - University of FloridaChristine N. Kay - University of FloridaXuan Liu - University of FloridaFrank M. Dyka - University of FloridaThomas C. Foster - University of FloridaYumiko Umino - SUNY Upstate Medical UniversitySukanya Karan - University of UtahSamuel G. Jacobson - Penn Presbyterian Medical CenterWolfgang Baehr - University of UtahAlexander Dizhoor - Salus UniversityWilliam W. Hauswirth - University of FloridaShannon E. Boye - Univ Florida, Coll Med, Dept Ophthalmol, Gainesville, FL 32610 USA
- Publication Details
- Human gene therapy, v 24(2), pp 189-202
- Publisher
- Mary Ann Liebert, Inc
- Number of pages
- 14
- Grant note
- Vision for Children CURE Formula Grant from Pennsylvania Department of Health Creed's Cause Foundation Lions of Central New York Foundation Fighting Blindness Macular Vision Research Foundation Eldon Family Foundation Research to Prevent Blindness, Inc.; Research to Prevent Blindness (RPB) EY13729; EY11123; EY08571; RR025777; P30-EY021721; EY11522 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Research to Prevent Blindness; Research to Prevent Blindness (RPB)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:000315196600009
- Scopus ID
- 2-s2.0-84874339776
- Other Identifier
- 991022035115404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental