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

  • Curated by eLife

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    Evaluation Summary:

    This authors used AAV in mouse retinas to express several candidate genes that they thought might have favorable effects on cone metabolism and therefore make cones more robust to stress caused by genetic deficiencies. Txnip is the most effective at prolonging cones survival and a combo of HK and PFK is the most effective at shortening cone survival. The investigators evaluated effects of specific mutations in Txnip with known biochemical effects. Their general conclusion is that Txnip may be enhancing mitochondrial function and ATP production and it may allow cones to use alternative fuels more effectively. This is an interesting and informative set of findings and it is presented and discussed in the context of what currently is known about retina metabolism and its influences on photoreceptor survival.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript.)

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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 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.

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  1. Version published to 10.7554/elife.66240 on eLife
  2. eLife

    Reviewer #2 (Public Review):

    In this manuscript, Xue et al. assessed many AAV vectors and demonstrated that Thioredoxin-interacting protein (TXNIP) saves RP cones by enhancing their lactate catabolism. The results of this study were based on cone counting, IHC and reporter. While the authors focus on the cellular metabolism in the Txnip-mediated rescue effect, it is unknown whether anti-oxidative stress plays a role as well.

  3. eLife

    Reviewer #1 (Public Review):

    The goal of this manuscript is to develop gene-agonistic approaches for promoting cone survival in retinal degenerative diseases. Based on their previous studies, the authors tested a total of 20 genes by subretinal delivery using an AAV vector which utilized a cone-specific promoter. Most of these genes augmented glucose utilization. Interestingly, only Txnip showed a positive result by prolonging cone survival (tested up to 50 days in rd1 retina). Txnip therapy also appears to be effective in rd10 and rho-/- retina. Additional strength of this study is the use of Txnip C247S allele that blocks its association with thioredoxin. Furthermore, additional work on how Txnip may contribute to cone survival by better utilization of lactate for energy is well presented though the conclusion on "heathier" mitochondria require additional data. This manuscript is potentially of great interest. The data are extensive and biological implications of the study are clear. However, the broad conclusions with respect of Txnip therapy for RP (or even AMD) are less than justified based on the data. Two weaknesses are apparent: the first is related to the method of quantification using whole mount retina, and the second related to the duration of the study. Immunostainings of retinal sections (and even TEMs) are critical to elucidate the structure of surviving cone photoreceptors (specially in the absence of rods) and their relationship to other cells (e.g., RPE, bipolar cells, glia). Similarly, Prusky's OMR can't be equated to visual acuity. The authors need to show cone structure/function at P50 and beyond (how long do the cones survive?) in rd1 and other models before claiming the potential benefit of Txnip for retinal and macular degeneration.

  4. eLife

    Evaluation Summary:

    This authors used AAV in mouse retinas to express several candidate genes that they thought might have favorable effects on cone metabolism and therefore make cones more robust to stress caused by genetic deficiencies. Txnip is the most effective at prolonging cones survival and a combo of HK and PFK is the most effective at shortening cone survival. The investigators evaluated effects of specific mutations in Txnip with known biochemical effects. Their general conclusion is that Txnip may be enhancing mitochondrial function and ATP production and it may allow cones to use alternative fuels more effectively. This is an interesting and informative set of findings and it is presented and discussed in the context of what currently is known about retina metabolism and its influences on photoreceptor survival.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript.)

  5. Version published to 10.1101/2021.01.27.428411v1 on bioRxiv