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Cited by 37Virus-based gene therapy researchRNA Interference and Gene DeliveryHearing, Cochlea, Tinnitus, Genetics

Dual-AAV delivery of large gene sequences to the inner ear

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Reisinger, Ellen·2020·Hearing Research
DOI 10.1016/j.heares.2019.107857
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Abstract

Adeno-associated viruses (AAVs) are preferred vectors for gene replacement therapy, as they are non-pathogenic, non-inflammatory, induce stable transgene expression in terminally differentiated cells, and a series of natural and engineered capsid proteins can be employed to target the vectors to specific cells. Only one feature of AAVs is limiting: the low cargo capacity for foreign DNA, restricting their application to coding sequences of <4 kb. In the last decade, splitting larger cDNAs into two AAVs and co-transducing tissue with such dual-AAV vectors has shown to result in the expression of the full-length protein in different tissues like retina, muscle and liver. This is due to the intrinsic capability of the AAV genomes to undergo homologous recombination and/or head-to-tail multimerization in nuclei of target cells. Recently, two groups independently found that a dual-AAV approach successfully delivered the 6 kb full-length otoferlin cDNA into inner hair cells of otoferlin knock-out mice and restored hearing. These pioneering studies pave the way for gene therapeutics that use dual-AAV vectors to restore hearing in forms of deafness caused by mutations in large genes.

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  • The inner ear is a confined compartment of the nervous system that has become the target of increasing gene therapy research efforts for oversized transgenes.

    “As is the case for the eye, the inner ear is a confined compartment of the nervous system that has become the target of increasing gene therapy research efforts for oversized transgenes [127].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [127]

    The Introduction describes gene delivery to inner-ear cells, and the Abstract reports recent dual-AAV delivery of a large gene sequence to inner hair cells, supporting the point about research on oversized transgenes. The passages do not characterize the inner ear as a confined compartment of the nervous system or establish that research efforts are increasing. (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Reisinger, E.
Affiliations
University of Tübingen (DE)
Corresponding author
Reisinger, Ellen
ORCID
Reisinger, Ellen
Venue
Hearing Research
Publisher
Elsevier BV
Published
2020-09
Volume
394
Pages
107857
ISSN
0378-5955 (ISSN-L)
DOI
10.1016/j.heares.2019.107857
OpenAlex
W2990626738
Cited by
37
References
15
Citations by year
2026: 2 · 2025: 4 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 6
FWCI
0.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Hearing Research (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
Keywords
adeno-associated virus, inner ear, otoferlin, inner hair cells, hearing loss, gene replacement therapy, homologous recombination, deafness
MeSH terms
Dependovirus, Animals, Genetic Vectors, Ear, Inner, Membrane Proteins, Genetic Therapy, Transgenes

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