Germline knockout of <i>Nr2e3</i> protects photoreceptors in three distinct mouse models of retinal degeneration.

Abstract

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting <i>Nr2e3</i>, a transcription factor required for the normal differentiation of rod photoreceptors. <i>Nr2e3</i> knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of <i>Nr2e3</i> potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient <i>Rho^-/-</i> mice), or abnormal phototransduction (phosphodiesterase-deficient <i>rd10</i> mice). <i>Nr2e3</i> knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by <i>Nr2e3</i> knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in <i>Nr2e3</i>-deficient rods may be responsible for the neuroprotective effects we observe.