NDLI: Long-term preservation of cone photoreceptors and restoration of cone function by gene therapy in the guanylate cyclase-1 knockout (GC1KO) mouse.

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Long-term preservation of cone photoreceptors and restoration of cone function by gene therapy in the guanylate cyclase-1 knockout (GC1KO) mouse.

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Long-term preservation of cone photoreceptors and restoration of cone function by gene therapy in the guanylate cyclase-1 knockout (GC1KO) mouse.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Dyka, Frank M. Hauswirth, William W. Pang, Jijing Boye, Shannon E. Conlon, Thomas Neeley, Andy Erger, Kirsten Boye, Sanford L. Ryals, Renee Cossette, Travis
Description	Country affiliation: United States Author Affiliation: Boye SL ( Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.)
Abstract	PURPOSE: The authors previously showed that subretinal delivery of AAV5 vectors containing murine guanylate cyclase-1 (GC1) cDNA driven by either photoreceptor-specific (hGRK1) or ubiquitous (smCBA) promoters was capable of restoring cone-mediated function and visual behavior and preserving cone photoreceptors in the GC1 knockout (GC1KO) mouse for 3 months. Here, the authors compared therapy conferred by the aforementioned vectors to that achieved with the highly efficient capsid tyrosine mutant AAV8(Y733F) and asked whether long-term therapy is achievable in this model. METHODS: AAV5-hGRK1-mGC1, AAV5-smCBA-mGC1, or AAV8(Y733F)-hGRK1-mGC1 was delivered subretinally to GC1KO mice between postnatal day (P)14 and P25. Retinal function was assayed by electroretinography. Localization of AAV-mediated GC1 expression and cone survival were assayed with immunohistochemistry, and the spread of vector genomes beyond the retina was quantified by PCR of optic nerve and brain tissue. RESULTS: Cone function was restored with all vectors tested, with AAV8(Y733F) being the most efficient. Electroretinographic responses were clearly measurable out to 1 year after treatment. AAV-mediated expression of GC1 was found exclusively in photoreceptors out to 15 months after injection. Cones were preserved for at least 11 months after treatment. AAV5- and AAV8(733)-delivered vector genomes were recovered primarily from optic nerve of the treated eye and, in only instance, from brain (1 of 20 samples). CONCLUSIONS: The authors demonstrate for the first time that long-term therapy (â ¼1 year) is achievable in a mammalian model of GC1 deficiency. These data provide additional justification for the development of an AAV-based gene therapy vector for the clinical treatment of Leber congenital amaurosis-1.
ISSN	01460404
e-ISSN	15525783
DOI	10.1167/iovs.11-7867
Journal	Investigative Opthalmology & Visual Science
Issue Number	10
Volume Number	52
Language	English
Publisher	Association for Research in Vision and Ophthalmology
Publisher Date	2011-09-09
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Dependovirus Genetics Genetic Therapy Genetic Vectors Guanylate Cyclase Leber Congenital Amaurosis Therapy Receptors, Cell Surface Retinal Cone Photoreceptor Cells Physiology Animals Cell Survival Disease Models, Animal Electroretinography G-protein-coupled Receptor Kinase 1 Heterotrimeric Gtp-binding Proteins Injections, Intraocular Physiopathology Mice Mice, Knockout Rna, Messenger Metabolism Reverse Transcriptase Polymerase Chain Reaction Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Ophthalmology
Content Type	Text
Resource Type	Article
Subject	Ophthalmology Sensory Systems Cellular and Molecular Neuroscience

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