RNA interference to reduce Egr1 expression in rods delays retinal degeneration in a model of retinitis pigmentosa.

Purpose: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases characterized by progressive photoreceptor degeneration. The early growth response-1 gene (Egr1) is an immediate-early gene implicated in neurodegenerative and stress responses in the retina, among many other tissues. While its expression is induced in the retina across various RP models, its functional role in the degenerative process remains unclear. This study aimed to investigate the contribution of Egr1 to photoreceptor degeneration in vivo.

Methods: We used adeno-associated virus (AAV)-mediated RNA interference and transgenic overexpression to modify Egr1 levels in rod and cone photoreceptors of wild-type and Rho^P23H/+ mice. Rod- and cone-specific promoters enabled cell-specific expression. Exposure to high levels of white light was used to induce retinal degeneration in wild-type mice. We assessed retinal structure and transgene expression through funduscopy, optical coherence tomography (OCT), immunofluorescence, and histological analysis. We measured Egr1 mRNA expression levels via real-time PCR and assessed the effects of Egr1 modulation on the retina by determining the thickness of the outer nuclear layer (ONL) and the number of surviving cones.

Results: Similar to other models of retinal degeneration, Egr1 was induced in the retina after light exposure and in the Rho^P23H/+ mouse during degeneration. AAV-mediated down- or upregulation of Egr1 in rods or cones did not affect retinal morphology in wild-type mice. In Rho^P23H/+ mice, Egr1 knockdown in rods modestly preserved ONL thickness up to 12 weeks after AAV injection. Overexpression did not accelerate degeneration beyond controls. Egr1 modulation in cones of wild-type or Rho^P23H/+ mice did not affect cone survival.

Conclusions: Egr1 upregulation is a consistent early marker of photoreceptor stress, independent of the nature of the underlying stimulus. Since moderate support for cell survival and preservation of retinal morphology was achieved through the downregulation of Egr1 expression in rods, but not in cones of the Rho^P23H/+ mouse, the function of EGR1 in degenerative processes may be cell type specific. Although Egr1 may contribute to disease progression, it is unlikely to be a causative factor for degeneration. Our findings underscore the complexity of the transcriptional response in retinal degeneration and suggest that Egr1 is a secondary effector of degenerative processes in rods.