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Alexander Kolesnikov, Daniel Murphy, Joseph Corbo, Vladimir Kefalov; Knockout of Nr2e3 protects against photoreceptor degeneration in two mouse models of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3135.
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In many retinal diseases such as retinitis pigmentosa (RP), single gene mutations cause rod photoreceptor death which is later followed by cone death. Traditionally, therapeutic efforts have aimed to reintroduce a normal copy of the mutated gene. However, RP is caused by mutations in dozens of different rod-specific or rod-enriched genes. Thus, there is a strong motivation to develop gene-independent therapies that could be used to treat a wide range of genetic forms of RP. While previous studies have shown the feasibility of this approach by targeting the rod-specific transcription factor Nrl, this disrupts gene expression and cases major changes in rod morphology and physiology. We tested the hypothesis that a more subtle approach, the knockout of Nr2e3 (a rod-specific transcription factor downstream of Nrl) will protect photoreceptors against degeneration in two different models of RP.
Rods in Nr2e3-deficient (rd7) mice are hybrid cells that ectopically express a subset of cone genes in addition to the normal complement of rod genes. We crossed rd7 mice with rhodopsin knockout (Rho-/-) or rod phosphodiesterase (rd10) mutant mice. Retinal function and morphology were analyzed at different ages by in vivo electroretinography and immunohistochemistry. Scotopic and photopic visual acuity and contrast sensitivity were evaluated from optomotor behavior tests. RNA-seq analysis was performed to determine differential gene expression in wild type and rd7 retinas.
ERG recordings revealed that M-cone function was preserved at wild-type levels for up to 6 months in Rho-/-;rd7 mice, in contrast to control Rho-/- animals where it deteriorated gradually and was fully absent by 4 months. This result correlated with greatly extended survival of both rods and cones and maintenance of photopic vision in the Rho-/-;rd7 mice. A similar degree of rod and cone structural and functional protection was observed in rd10;rd7 mice despite the very rapid retinal degeneration in rd10 mice. RNA-seq analysis showed up-regulation of several cone genes in rd7 retinas which might mediate protection against retinal degeneration.
Knockout of Nr2e3 slows retinal degeneration and ameliorates secondary cone death in two distinct models of RP. The therapeutic mechanism may involve the upregulation of one or more cone-enriched genes in rods.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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