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Cited by 34Retinal Development and DisordersVirus-based gene therapy researchRNA Interference and Gene Delivery

Myosin7a Deficiency Results in Reduced Retinal Activity Which Is Improved by Gene Therapy

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Colella, Pasqualina, Sommella, Andrea, Marrocco, Elena, Di Vicino, Umberto, Polishchuk, Elena, Garrido, Marina Garcia, Seeliger, Mathias W., Polishchuk, Roman +1 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0072027PMC PMC3753344
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Abstract

Mutations in MYO7A cause autosomal recessive Usher syndrome type IB (USH1B), one of the most frequent conditions that combine severe congenital hearing impairment and retinitis pigmentosa. A promising therapeutic strategy for retinitis pigmentosa is gene therapy, however its pre-clinical development is limited by the mild retinal phenotype of the shaker1 (sh1(-/-)) murine model of USH1B which lacks both retinal functional abnormalities and degeneration. Here we report a significant, early-onset delay of sh1(-/-) photoreceptor ability to recover from light desensitization as well as a progressive reduction of both b-wave electroretinogram amplitude and light sensitivity, in the absence of significant loss of photoreceptors up to 12 months of age. We additionally show that subretinal delivery to the sh1(-/-) retina of AAV vectors encoding the large MYO7A protein results in significant improvement of sh1(-/-) photoreceptor and retinal pigment epithelium ultrastructural anomalies which is associated with improvement of recovery from light desensitization. These findings provide new tools to evaluate the efficacy of experimental therapies for USH1B. In addition, although AAV vectors expressing large genes might have limited clinical applications due to their genome heterogeneity, our data show that AAV-mediated MYO7A gene transfer to the sh1(-/-) retina is effective.

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  • Subretinal injection of single oversized AAV2/2 and AAV2/5 vectors has shown retinal transduction and phenotype correction.

    “For instance, subretinal injection of single oversized AAV2/2 and AAV2/5 vectors has shown retinal transduction and phenotype correction, indicating that fragmented genomes could reconstitute the full-length cDNA post-infection [97,98].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [97]

    The Results and Discussion report that subretinal oversized AAV2/5-hMYO7A delivery produced retinal expression and improved defects in sh1−/− mice. The Methods specify that AAV2/2 was used for in vitro experiments, not the retinal rescue experiments. The Discussion also says that reassembly of fragmented genomes is one possible explanation, but the mechanism remains unresolved (page numbers unavailable in our copy). (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Fragmented genomes could reconstitute the full-length cDNA post-infection.

    “indicating that fragmented genomes could reconstitute the full-length cDNA post-infection [97,98]”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [97]

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References 64 · Cited by 34

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Authors
Colella, P., Sommella, A., Marrocco, E., Di Vicino, U., Polishchuk, E., Garrido, M. G., Seeliger, M. W., Polishchuk, R., & Auricchio, A.
Affiliations
Telethon Institute Of Genetics And Medicine (IT)
Corresponding author
Auricchio, Alberto
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-08-26
Volume
8
Issue
8
Pages
e72027
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0072027
PMC
PMC3753344
OpenAlex
W2111728551
Cited by
34
References
64
Citations by year
2026: 1 · 2025: 2 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 9
FWCI
2.24
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • European Commission
  • National Institutes of Health (R24 RY019861-01A)
  • U.S. Public Health Service (R24 RY019861-01A)
  • National Eye Institute (R24EY019861)
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
MYO7A, retinitis pigmentosa, electroretinogram, AAV gene therapy, subretinal gene delivery, congenital hearing loss, retinal function
MeSH terms
Myosin VIIa, Dependovirus, Adult, Animals, Disease Models, Animal, Electroretinography, Eye, Female, Genetic Vectors, Humans, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Microscopy, Electron, Myosins, Retina, Retinal Degeneration, Blotting, Western, Genetic Therapy, Mice, Knockout, Melanosomes, Mice, Usher Syndromes, HEK293 Cells

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