miR-181a/b downregulation: a possible gene-independent therapeutic approach for inherited retinal diseases

Abstract

Purpose : Inherited retinal diseases (IRDs), characterized by progressive photoreceptor (PRs) cell death, represent a significant cause of visual impairment in the Western population. Their broad genetic heterogeneity constitutes an important limitation to the development of gene-specific therapies. Therefore, there is a strong need for the implementation of effective gene-independent therapeutic strategies, targeting common dysregulated pathways, which can be of benefit for a significant fraction of IRD patients. In this respect, microRNAs are promising tools, due to their capability to simultaneously fine tune modulating multiple molecular pathways involved in IRD pathogenesis and progression. Recently, we discovered that miR-181a/b inactivation enhances mitochondrial turnover in the retina through the coordinated activation of mitochondrial biogenesis and mitophagy and protects retinal ganglion cells from cell death in in vivo models of Leber's hereditary optic neuropathy (LHON). We aimed at demonstrating that miR-181a/b downregulation exerts a protective effect in IRD models as well.

Methods : We tested the effect of miR-181a/b downregulation in two mouse IRD models: the transgenic RHO-P347S, a model for an autosomal dominant form of Retinitis Pigmentosa, and the Abca4^-/- mouse, a model for Stargardt disease. We used either a genetic approach by crossing the above models with a miR-181a/b-1^-/- mouse or through subretinal delivery of an adeno-associated viral (AAV) vector carrying a miR-181a/b inhibitor sequence (AAV-GFP-Sponge-miR-181a/b).

Results : We found that reduction of miR-181a/b levels in RHO-P347S mice a) improves mitochondrial mass and morphology; b) decreases PR cell death and c) ameliorates the structure of PR outer segments which results in enhancement of visual function. Moreover, we found that miR-181a/b downregulation significantly decreases lipofuscin accumulation in the retinal pigment epithelium of Abca4^-/- mice. In addition, the therapeutic potential of AAV-GFP-Sponge-miR-181a/b was validated also in LHON mouse model.

Conclusions : Overall, our data support the gene-independent protection exerted by miR-181a/b inhibition in IRDs and highlight the potential use of AAV-GFP-Sponge-miR-181a/b vectors as effective and innovative therapeutic tools for these conditions, both in slowing down disease progression and in supporting gene-dependent therapeutic procedures.

This is a 2020 ARVO Annual Meeting abstract.