Document Detail


AAV-mediated gene therapy in the guanylate cyclase (RetGC1/RetGC2) double knockout mouse model of Leber congenital amaurosis.
MedLine Citation:
PMID:  23210611     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Sanford L Boye; Igor V Peshenko; Wei Chieh Huang; Seok Hong Min; Issam McDoom; Christine N Kay; Xuan Liu; Frank M Dyka; Thomas C Foster; Yumiko Umino; Sukanya Karan; Samuel G Jacobson; Wolfgang Baehr; Alexander Dizhoor; William W Hauswirth; Shannon E Boye
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Human gene therapy     Volume:  24     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-20     Completed Date:  2013-09-10     Revised Date:  2014-05-21    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  189-202     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Dependovirus / genetics,  metabolism*
Enzyme Activation
G-Protein-Coupled Receptor Kinase 1 / genetics,  metabolism
Gene Transfer Techniques
Genetic Therapy / methods*
Genetic Vectors / administration & dosage
Guanylate Cyclase / administration & dosage*,  genetics,  metabolism
Humans
Leber Congenital Amaurosis / pathology,  therapy*
Maze Learning
Mice
Mice, Inbred C57BL
Mice, Knockout
Promoter Regions, Genetic
Receptors, Cell Surface / administration & dosage*,  genetics,  metabolism
Retina / enzymology,  pathology
Retinal Cone Photoreceptor Cells / enzymology,  pathology
Retinal Rod Photoreceptor Cells / enzymology,  pathology
Tomography, Optical Coherence
Grant Support
ID/Acronym/Agency:
EY08571/EY/NEI NIH HHS; EY11123/EY/NEI NIH HHS; EY11522/EY/NEI NIH HHS; EY13729/EY/NEI NIH HHS; P30 EY014800/EY/NEI NIH HHS; P30 EY021721/EY/NEI NIH HHS; P30-EY021721/EY/NEI NIH HHS; R01 AG014979/AG/NIA NIH HHS; R01 EY011522/EY/NEI NIH HHS; R37 AG036800/AG/NIA NIH HHS; RR025777/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Receptors, Cell Surface; EC 2.7.11.14/G-Protein-Coupled Receptor Kinase 1; EC 2.7.11.14/GRK1 protein, human; EC 4.6.1.2/Guanylate Cyclase; EC 4.6.1.2/Gucy2d protein, mouse; EC 4.6.1.2/Gucy2e protein, mouse
Comments/Corrections

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