AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa
- Harvard Medical School, United States
- 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.
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RP mouse cone transcriptom change with Txnip treatmentNCBI Gene Expression Omnibus, GSE161622.
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Wildtype (wt) mouse cone transcriptome change with Txnip treatmentNCBI Gene Expression Omnibus, GSE168503.
Article and author information
Author details
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).
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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AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa
eLife 10:e66240.
https://doi.org/10.7554/eLife.66240
