Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis.

Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Research Abstract Details 

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Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Abstract Text:

Alejandro J Roman,Sanford L Boye,Tomas S Aleman,Ji-jing Pang,J Hugh McDowell,Shannon E Boye,Artur V Cideciyan,Samuel G Jacobson,William W Hauswirth,

PURPOSE: Dramatic restoration of retinal function has followed subretinal viral-mediated gene therapy in RPE65-deficient animal models of human Leber congenital amaurosis (LCA) caused by RPE65 mutations. Progress in early-phase clinical trials of RPE65-LCA prompted us to begin development of an in vivo bioassay of clinical grade vector stability for later-phase trials. METHODS: Naturally-occurring Rpe65-mutant rd12 mice (2-4 mo of age) were studied with full-field electroretinograms (ERGs). Flash stimuli (range, -4.1 to 3.6 log scot-cd x s x m(-2)) were used to evoke ERGs in anesthetized, dark-adapted mice. B-wave amplitudes were measured conventionally and luminance-response functions were fit. Leading edges of photoresponses were analyzed with a model of rod phototransduction activation. A unilateral subretinal injection of AAV2-CB(SB)-hRPE65 vector was delivered and therapeutic efficacy of 4 doses spanning a 2 log unit range was studied with ERGs performed about 6 weeks after injection. Uninjected rd12 eyes and wild-type (wt) mice served as controls. RESULTS: Rd12 mice showed substantially smaller amplitudes and lower sensitivities than wt mice for all measured ERG b-wave and photoresponse parameters. For the dose-response study, there was no difference between 0.01X-dosed mice and untreated mutants. Improved receptoral and post-receptoral function was evident for 0.1X, 0.3X, 1X doses: b-wave semi-saturation constants decreased, b-wave amplitudes increased with dose; photoresponses showed faster kinetics and higher maximum amplitudes. ERG b-wave amplitude to a selected stimulus light intensity could provide evidence of biologic activity of the vector; interocular differences in b-wave amplitude comparing treated versus untreated eyes in the same animal also revealed vector efficacy. CONCLUSIONS: We have taken the first steps toward developing an ERG assay of biologic activity of human grade vector for future clinical trials of RPE65-LCA. Faithful murine models of treatable human disease tested with specific ERG protocols may emerge as valuable in vivo bioassays for future human clinical trials of therapy in many retinal degenerative diseases.

Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Publishing Authors By Initials

AJ Roman,SL Boye,TS Aleman,JJ Pang,JH McDowell,SE Boye,AV Cideciyan,SG Jacobson,WW Hauswirth,

For similar eye diseases: retinal diseases: retinal degeneration research abstracts see: eye diseases: retinal diseases: retinal degeneration research

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Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular vision

VOLUME: 13

Page Numbers: 1701-10

Journal Abbreviation: Mol. Vis.

ISSN: 1090-0535

DAY: 18

MONTH: 09

YEAR: 2007

Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Information

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LANGUAGE: eng

NlmUniqueID: 9605351

Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Keywords Mesh Terms:

KEYWORDS: Retinal Degeneration

MESH TERMS: therapy

Chemical & Substance for Abstract: Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Information

Substance Name: Rpe65 protein, mouse

Registry Number: 0

Grant and Affiliation Information for Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis.

AFFILIATION: Department of Ophthalmology, Scheie Eye Institute, Philadelphia, PA, USA.

Country: United States

AGENCY: United States NEI

GRANT: P30EY001583

ACRONYM: EY

MEDLINETA: Mol Vis

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