CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype

E R Burnight; L A Wiley; A V Drack; T A Braun; K R Anfinson; E E Kaalberg; J A Halder; L M Affatigato; R F Mullins; E M Stone; B A Tucker

doi:10.1038/gt.2014.39

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CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype

Journal article

Open access

Peer reviewed

CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype

E R Burnight, L A Wiley, A V Drack, T A Braun, K R Anfinson, E E Kaalberg, J A Halder, L M Affatigato, R F Mullins, E M Stone, …

Gene therapy, Vol.21(7), pp.662-672

07/2014

DOI: 10.1038/gt.2014.39

PMCID: PMC4188442

PMID: 24807808

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Abstract

Mutations in CEP290 are the most common cause of Leber congenital amaurosis (LCA), a severe inherited retinal degenerative disease for which there is currently no cure. Autosomal recessive CEP290-associated LCA is a good candidate for gene replacement therapy, and cells derived from affected individuals give researchers the ability to study human disease and therapeutic gene correction in vitro. Here we report the development of lentiviral vectors carrying full-length CEP290 for the purpose of correcting the CEP290 disease-specific phenotype in human cells. A lentiviral vector containing CMV-driven human full-length CEP290 was constructed. Following transduction of patient-specific, iPSC-derived, photoreceptor precursor cells, reverse transcriptase-PCR analysis and western blotting revealed vector-derived expression. As CEP290 is important in ciliogenesis, the ability of fibroblast cultures from CEP290-associated LCA patients to form cilia was investigated. In cultures derived from these patients, fewer cells formed cilia compared with unaffected controls. Cilia that were formed were shorter in patient-derived cells than in cells from unaffected individuals. Importantly, lentiviral delivery of CEP290 rescued the ciliogenesis defect. The successful construction and viral transfer of full-length CEP290 brings us closer to the goal of providing gene- and cell-based therapies for patients affected with this common form of LCA.

Leber Congenital Amaurosis - pathology

Retina - metabolism

Humans

Neoplasm Proteins - metabolism

Antigens, Neoplasm - metabolism

Lentivirus - genetics

Neoplasm Proteins - genetics

Leber Congenital Amaurosis - therapy

Disease Models, Animal

Fibroblasts - metabolism

Induced Pluripotent Stem Cells - metabolism

Induced Pluripotent Stem Cells - pathology

Antigens, Neoplasm - genetics

Cilia - pathology

Transduction, Genetic

Induced Pluripotent Stem Cells - transplantation

Cells, Cultured

Leber Congenital Amaurosis - genetics

Fibroblasts - pathology

Cilia - metabolism

Animals

Genetic Vectors - pharmacology

Photoreceptor Cells - metabolism

Mice

Retina - pathology

Details

Title: Subtitle: CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype
Creators: E R Burnight - University of Iowa
L A Wiley - University of Iowa, Ophthalmology and Visual Sciences
A V Drack - University of Iowa, Ophthalmology and Visual Sciences
T A Braun - University of Iowa, Ophthalmology and Visual Sciences
K R Anfinson - University of Iowa
E E Kaalberg - University of Iowa, Ophthalmology and Visual Sciences
J A Halder - University of Iowa
L M Affatigato - University of Iowa
R F Mullins - University of Iowa, Ophthalmology and Visual Sciences
E M Stone - University of Iowa, Ophthalmology and Visual Sciences
B A Tucker - University of Iowa, Ophthalmology and Visual Sciences
Resource Type: Journal article
Publication Details: Gene therapy, Vol.21(7), pp.662-672
DOI: 10.1038/gt.2014.39
PMID: 24807808
PMCID: PMC4188442
NLM abbreviation: Gene Ther
ISSN: 0969-7128
eISSN: 1476-5462
Publisher: England
Grant note: DP2 OD007483 / NIH HHS 1-DP2-OD007483-01 / NIH HHS Howard Hughes Medical Institute R01 EY017451 / NEI NIH HHS 1F32-EY022834-01 / NEI NIH HHS F32 EY022834 / NEI NIH HHS NEI EY017451 / NEI NIH HHS
Language: English
Date published: 07/2014
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983979993702771

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