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Cited by 56Retinal Development and DisordersVirus-based gene therapy researchRetinal Diseases and Treatments

Dual ABCA4 -AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease

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Dyka, Frank M., Molday, Laurie L., Chiodo, Vince A., Molday, Robert S., Hauswirth, William W.·2019·Human Gene Therapy
DOI 10.1089/hum.2019.132PMC PMC6854433
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Abstract

Autosomal recessive Stargardt disease is the most common inherited macular degeneration in humans. It is caused by mutations in the retina-specific ATP binding cassette transporter A4 (ABCA4) that is essential for the clearance of all-trans-retinal from photoreceptor cells. Loss of this function results in the accumulation of toxic bisretinoids in the outer segment disk membranes and their subsequent transfer into adjacent retinal pigment epithelium (RPE) cells. This ultimately leads to the Stargardt disease phenotype of increased retinal autofluorescence and progressive RPE and photoreceptor cell loss. Adeno-associated virus (AAV) vectors have been widely used in gene therapeutic applications, but their limited cDNA packaging capacity of ∼4.5 kb has impeded their use for transgenes exceeding this limit. AAV dual vectors were developed to overcome this size restriction. In this study, we have evaluated the in vitro expression of ABCA4 using three options: overlap, transplicing, and hybrid ABCA4 dual vector systems. The hybrid system was the most efficient of these dual vector alternatives and used to express the full-length ABCA4 in Abca4−/− mice. The full-length ABCA4 protein correctly localized to photoreceptor outer segments. Moreover, treatment of Abca4−/− mice with this ABCA4 hybrid dual vector system resulted in a reduced accumulation of the lipofuscin/N-retinylidene-N-retinylethanolamine (A2E) autofluorescence in vivo, and retinal A2E quantification supported these findings. These results show that the hybrid AAV dual vector option is both safe and therapeutic in mice, and the delivered ABCA4 transgene is functional and has a significant effect on reducing A2E accumulation in the Abca4−/− mouse model of Stargardt disease.

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  • Some studies have revealed amelioration of retinal phenotypes in STGD1 mouse models.

    “Although some of these studies have revealed amelioration of retinal phenotypes in STGD1 mouse models [29,64,102], the low transduction efficiencies as well as the aberrant production of truncated proteins from single AAV vectors have been two major limitations [103,104].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [102]

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Cited by

Sorted by citations

Authors
Dyka, F. M., Molday, L. L., Chiodo, V. A., Molday, R. S., & Hauswirth, W. W.
Affiliations
  • University of Florida (US)
  • University of British Columbia (CA)
Corresponding author
Dyka, Frank M.
ORCID
Venue
Human Gene Therapy
Publisher
SAGE Publications
Published
2019-11-01
Volume
30
Issue
11
Pages
1361-1370
ISSN
  • 1043-0342 (ISSN-L)
  • 1557-7422
DOI
10.1089/hum.2019.132
PMC
PMC6854433
OpenAlex
W2967945233
Cited by
56
References
20
Citations by year
2026: 5 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 8 · 2021: 13 · 2020: 8 · 2019: 1
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations
  • Human Gene Therapy (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Keywords
ABCA4, all-trans-retinal, retinal autofluorescence, lipofuscin, retinal pigment epithelium, photoreceptor outer segments, gene therapy
MeSH terms
Stargardt Disease, Dependovirus, Animals, Disease Models, Animal, Fluorescence, Fundus Oculi, Genes, Recessive, Genetic Vectors, Humans, Mice, Inbred C57BL, Retina, Retinoids, ATP-Binding Cassette Transporters, HEK293 Cells

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