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AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

  1. Yunlu Xue
  2. Sean K Wang
  3. Parimal Rana
  4. Emma R West
  5. Christin M Hong
  6. Helian Feng
  7. David M Wu
  8. Constance L Cepko  Is a corresponding author
  1. Harvard Medical School, United States
  2. Harvard T H Chan School of Public Health, United States
Research Article
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Cite this article as: eLife 2021;10:e66240 doi: 10.7554/eLife.66240

Abstract

Retinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE161622 and GSE168503.

The following data sets were generated

Article and author information

Author details

  1. Yunlu Xue

    Department of Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2088-9826
  2. Sean K Wang

    Genetics and Ophthalmology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Parimal Rana

    Genetics and Ophthalmology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Emma R West

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christin M Hong

    Genetics and Ophthalmology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Helian Feng

    Biostatistics, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. David M Wu

    Department of Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Constance L Cepko

    Department of Genetics, Harvard Medical School, Boston, United States
    For correspondence
    cepko@genetics.med.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9945-6387

Funding

National Eye Institute (K99EY030951)

  • Yunlu Xue

National Eye Institute (U01EY025497)

  • Constance L Cepko

Alcon Research Institute

  • Constance L Cepko

Astellas Pharmaceuticals

  • Constance L Cepko

Howard Hughes Medical Institute

  • Constance L Cepko

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the IACUC of Harvard University in accordance with institutional guidelines (protocol number: IS1695).

Reviewing Editor

  1. Claude Desplan, New York University, United States

Publication history

  1. Received: January 5, 2021
  2. Accepted: March 30, 2021
  3. Accepted Manuscript published: April 13, 2021 (version 1)
  4. Version of Record published: April 28, 2021 (version 2)

Copyright

© 2021, Xue et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

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    Bilge E Öztürk et al.
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    Background:

    Adeno-associated virus (AAV)-mediated gene therapies are rapidly advancing to the clinic, and AAV engineering has resulted in vectors with increased ability to deliver therapeutic genes. Although the choice of vector is critical, quantitative comparison of AAVs, especially in large animals, remains challenging.

    Methods:

    Here, we developed an efficient single-cell AAV engineering pipeline (scAAVengr) to simultaneously quantify and rank efficiency of competing AAV vectors across all cell types in the same animal.

    Results:

    To demonstrate proof-of-concept for the scAAVengr workflow, we quantified – with cell-type resolution – the abilities of naturally occurring and newly engineered AAVs to mediate gene expression in primate retina following intravitreal injection. A top performing variant identified using this pipeline, K912, was used to deliver SaCas9 and edit the rhodopsin gene in macaque retina, resulting in editing efficiency similar to infection rates detected by the scAAVengr workflow. scAAVengr was then used to identify top-performing AAV variants in mouse brain, heart, and liver following systemic injection.

    Conclusions:

    These results validate scAAVengr as a powerful method for development of AAV vectors.

    Funding:

    This work was supported by funding from the Ford Foundation, NEI/NIH, Research to Prevent Blindness, Foundation Fighting Blindness, UPMC Immune Transplant and Therapy Center, and the Van Sloun fund for canine genetic research.

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