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

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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  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
(2021)
AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa
eLife 10:e66240.
https://doi.org/10.7554/eLife.66240

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