Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness

Defne Amado; Federico Mingozzi; Daniel Hui; Jeannette L Bennicelli; Zhangyong Wei; Yifeng Chen; Erin Bote; Rebecca L Grant; Jeffrey A Golden; Kristina Narfstrom; Nasreen A Syed; Stephen E Orlin; Katherine A High; Albert M Maguire; Jean Bennett

doi:10.1126/scitranslmed.3000659

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Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness

Journal article

Open access

Peer reviewed

Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness

Defne Amado, Federico Mingozzi, Daniel Hui, Jeannette L Bennicelli, Zhangyong Wei, Yifeng Chen, Erin Bote, Rebecca L Grant, Jeffrey A Golden, Kristina Narfstrom, …

Science translational medicine, Vol.2(21), 21ra16

03/03/2010

DOI: 10.1126/scitranslmed.3000659

PMCID: PMC4169124

PMID: 20374996

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Abstract

Leber's congenital amaurosis (LCA) is a group of severe inherited retinal degenerations that are symptomatic in infancy and lead to total blindness in adulthood. Recent clinical trials using recombinant adeno-associated virus serotype 2 (rAAV2) successfully reversed blindness in patients with LCA caused by RPE65 mutations after one subretinal injection. However, it was unclear whether treatment of the second eye in the same manner would be safe and efficacious, given the potential for a complicating immune response after the first injection. Here, we evaluated the immunological and functional consequences of readministration of rAAV2-hRPE65v2 to the contralateral eye using large animal models. Neither RPE65-mutant (affected; RPE65(-/-)) nor unaffected animals developed antibodies against the transgene product, but all developed neutralizing antibodies against the AAV2 capsid in sera and intraocular fluid after subretinal injection. Cell-mediated immune responses were benign, with only 1 of 10 animals in the study developing a persistent T cell immune response to AAV2, a response that was mediated by CD4(+) T cells. Sequential bilateral injection caused minimal inflammation and improved visual function in affected animals. Thus, subretinal readministration of rAAV2 in animals is safe and effective, even in the setting of preexisting immunity to the vector, a parameter that has been used to exclude patients from gene therapy trials.

Immunohistochemistry

Dependovirus - genetics

Genetic Therapy

Genetic Vectors - administration & dosage

Humans

Middle Aged

Genetic Vectors - adverse effects

Antibodies, Neutralizing - immunology

Aged, 80 and over

Primates

Adult

Blindness - congenital

Blindness - therapy

Eye Proteins - genetics

Carrier Proteins - therapeutic use

cis-trans-Isomerases

Drug Administration Routes

Immunity - immunology

Treatment Outcome

Eye Proteins - therapeutic use

Blindness - genetics

Anterior Chamber - immunology

Capsid - immunology

Carrier Proteins - genetics

Animals

Dogs

Titrimetry

Aged

Postmortem Changes

Retina - pathology

Details

Title: Subtitle: Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness
Creators: Defne Amado - F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
Federico Mingozzi
Daniel Hui
Jeannette L Bennicelli
Zhangyong Wei
Yifeng Chen - Children's Hospital of Philadelphia
Erin Bote
Rebecca L Grant
Jeffrey A Golden
Kristina Narfstrom
Nasreen A Syed
Stephen E Orlin
Katherine A High
Albert M Maguire
Jean Bennett
Resource Type: Journal article
Publication Details: Science translational medicine, Vol.2(21), 21ra16
DOI: 10.1126/scitranslmed.3000659
PMID: 20374996
PMCID: PMC4169124
NLM abbreviation: Sci Transl Med
ISSN: 1946-6234
eISSN: 1946-6242
Publisher: United States
Grant note: 1F30AG030961 / NIA NIH HHS F30 AG030961 / NIA NIH HHS Howard Hughes Medical Institute P30 EY001583 / NEI NIH HHS
Language: English
Date published: 03/03/2010
Academic Unit: Pathology; Ophthalmology and Visual Sciences
Record Identifier: 9983980065802771

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