miR-204 overexpression exerts a protective role in inherited retinal diseases

Purpose : Inherited retinal diseases (IRDs) are progressive neurodegenerative conditions of the retina that represent a main cause of genetic blindness in the Western world. Their high genetic heterogeneity hinders the development of effective gene-based therapies. We have recently demonstrated that the microRNA miR-204 is essential for retinal function and plays a pathogenic role in IRD in humans. Therefore, we aimed at assessing the potential therapeutic action of this microRNA in IRDs. Methods : We delivered by subretinal injection an adeno-associated viral vector carrying the miR-204 precursor to the Aipl1knockout and the P347S-RHOtransgenic mouse lines, models of autosomal recessive and dominant forms of IRDs, respectively. The impact on retinal function and degeneration was assessed by electroretinographic and immunohistological analyses. Results : We detected a notable improvement of the ERG response in the miR-204-injected eyes of P347S-RHOmice. This effect persisted for two months post-injection and was prevalent in conditions reflecting mixed cone-rod responses. We also observed a preservation of cone photoreceptors and a significant decrease in apoptotic photoreceptor cells. Photoreceptors were better preserved also in miR204-injected eyes of Aipl1 knockoutmice. Transcriptome analysis suggested that dampening of microglia activation represents one of the main mechanisms underlying the neuroprotective effect of miR-204. Conclusions : Our findings indicate that the subretinal delivery of miR-204 attenuates retinal degeneration in IRD mouse models and preserves retinal function, supporting the gene-independent therapeutic potential of this microRNA.