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Cited by 128Virus-based gene therapy researchRetinal Development and DisordersRNA Interference and Gene Delivery

Triple Vectors Expand AAV Transfer Capacity in the Retina

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Maddalena, Andrea, Tornabene, Patrizia, Tiberi, Paola, Minopoli, Renato, Manfredi, Anna, Mutarelli, Margherita, Rossi, Settimio, Simonelli, Francesca +3 more·2018·Molecular Therapy
DOI 10.1016/j.ymthe.2017.11.019PMC PMC5835116
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Abstract

Retinal gene transfer with adeno-associated viral (AAV) vectors holds great promise for the treatment of inherited retinal degenerations (IRDs). One limit of AAV is its transfer capacity of about 5 kb, which can be expanded to about 9 kb, using dual AAV vectors. This strategy would still not suffice for treatment of IRDs such as Usher syndrome type 1D or Alström syndrome type I (ALMS) due to mutations in CDH23 or ALMS1, respectively. To overcome this limitation, we generated triple AAV vectors, with a maximal transfer capacity of about 14 kb. Transcriptomic analysis following triple AAV transduction showed the expected full-length products along a number of aberrant transcripts. However, only the full-length transcripts are efficiently translated in vivo. We additionally showed that approximately 4% of mouse photoreceptors are transduced by triple AAV vectors and showed correct localization of recombinant ALMS1. The low-photoreceptor transduction levels might justify the modest and transient improvement we observe in the retina of a mouse model of ALMS. However, the levels of transduction mediated by triple AAV vectors in pig retina reached 40% of those observed with single vectors, and this bodes well for further improving the efficiency of triple AAV vectors in the retina.

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Authors
Maddalena, A., Tornabene, P., Tiberi, P., Minopoli, R., Manfredi, A., Mutarelli, M., Rossi, S., Simonelli, F., Naggert, J. K., Cacchiarelli, D., & Auricchio, A.
Affiliations
  • Telethon Institute Of Genetics And Medicine (IT)
  • University of Campania "Luigi Vanvitelli" (IT)
Corresponding author
Auricchio, Alberto
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2018-02
Volume
26
Issue
2
Pages
524-541
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2017.11.019
PMC
PMC5835116
OpenAlex
W2771095058
Cited by
128
References
15
Citations by year
2026: 8 · 2025: 16 · 2024: 12 · 2023: 13 · 2022: 13 · 2021: 15 · 2020: 22 · 2019: 20 · 2018: 9
FWCI
9.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
  • Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
Funders
  • European Research Council (282085, 694323)
  • European Union (FP7 291778 "DTI-IMPORT")
  • Italian Telethon Foundation (TGM16MT1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
adeno-associated virus vectors, transfer capacity, retinal gene transfer, inherited retinal degeneration, ALMS1, CDH23, photoreceptors, aberrant transcripts, pig retina
MeSH terms
Dependovirus, Animals, Genetic Vectors, Humans, Recombination, Genetic, Retina, Swine, Transcription, Genetic, Transduction, Genetic, Genetic Therapy, Cadherins, Gene Expression, Gene Expression Regulation, Viral, Genes, Reporter, Gene Transfer Techniques, Mice, Knockout, Transgenes, Mice, HEK293 Cells

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