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An AAV Dual Vector Strategy Ameliorates the Stargardt Phenotype in Adult Abca4-/- Mice.

Authors
  • McClements, Michelle E1
  • Barnard, Alun R1
  • Singh, Mandeep S2
  • Charbel Issa, Peter1, 3
  • Jiang, Zhichun4
  • Radu, Roxana A4
  • MacLaren, Robert E1, 3
  • 1 1 Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. , (United Kingdom)
  • 2 2 John Hopkins University, Baltimore, MD.
  • 3 3 Oxford Eye Hospital, Oxford, United Kingdom. , (United Kingdom)
  • 4 4 Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
Type
Published Article
Journal
Human Gene Therapy
Publisher
Mary Ann Liebert
Publication Date
May 01, 2019
Volume
30
Issue
5
Pages
590–600
Identifiers
DOI: 10.1089/hum.2018.156
PMID: 30381971
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The recent approval in the United States of the first adeno-associated viral (AAV) vector for the treatment of an inherited retinal degeneration validates this approach for the treatment of many other diseases. A major limiting factor continues to be the size restriction of the AAV transgene at under 5 kb. Stargardt disease is the most prevalent form of recessively inherited blindness and is caused by mutations in ABCA4, the gene that codes for ATP-binding cassette transporter protein family member 4, which has a coding sequence length of 6.8 kb. Dual vector approaches increase the capacity of AAV gene therapy, but at the cost of substantially reduced levels of target protein, which may be insufficient to achieve a therapeutic effect. Here we show that the efficacy of recombination of dual vectors is dependent on the length of DNA overlap between two transgenes. With optimized recombination, full-length ABCA4 protein is expressed in the photoreceptor outer segments of Abca4-/- mice at levels sufficient to reduce bisretinoid formation and correct the autofluorescent phenotype. These observations support a dual vector approach in future clinical trials using AAV gene therapy to treat Stargardt disease.

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