AAV-miR-204 Protects from Retinal Degeneration by Attenuation of Microglia Activation and Photoreceptor Cell Death

Marianthi Karali,Irene Guadagnino,Elena Marrocco,Rossella De Cegli,Annamaria Carissimo,Mariateresa Pizzo,Simona Casarosa,Ivan Conte,Enrico Maria Surace,Sandro Banfi

doi:10.1016/j.omtn.2019.11.005

Abstract

Inherited retinal diseases (IRDs) represent a frequent cause of genetic blindness. Their high genetic heterogeneity hinders the application of gene-specific therapies to the vast majority of patients. We recently demonstrated that the microRNA miR-204 is essential for retinal function, although the underlying molecular mechanisms remain poorly understood. Here, we investigated the therapeutic potential of miR-204 in IRDs. We subretinally delivered an adeno-associated viral (AAV) vector carrying the miR-204 precursor to two genetically different IRD mouse models. The administration of AAV-miR-204 preserved retinal function in a mouse model for a dominant form of retinitis pigmentosa (RHO-P347S). This was associated with a reduction of apoptotic photoreceptor cells and with a better preservation of photoreceptor marker expression. Transcriptome analysis showed that miR-204 shifts expression profiles of transgenic retinas toward those of healthy retinas by the downregulation of microglia activation and photoreceptor cell death. Delivery of miR-204 exerted neuroprotective effects also in a mouse model of Leber congenital amaurosis, due to mutations of the Aipl1 gene. Our study highlights the mutation-independent therapeutic potential of AAV-miR204 in slowing down retinal degeneration in IRDs and unveils the previously unreported role of this miRNA in attenuating microglia activation and photoreceptor cell death.

Highlights

Inherited retinal diseases (IRDs), including among others, retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), cone and cone-rod dystrophies, and macular dystrophies, are the most important causes of vision impairment in the working-age population
We looked at microglia activation in RHO-P347S mice by double immunostaining for antiionized calcium-binding adaptor molecule 1 (Iba1) and either CD68 or major histocompatibility complex class II (MHCII) at PN30 (Figure 4A; data not shown)
This study demonstrates that delivery of miR-204 in the subretinal space attenuates photoreceptor degeneration in two genetically different IRD mouse models. miR-204 exerts its neuroprotective effect by acting on common pathways to which IRDs converge, irrespective of the initial disease-causing mutation

Summary

Introduction

Inherited retinal diseases (IRDs), including among others, retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), cone and cone-rod dystrophies, and macular dystrophies, are the most important causes of vision impairment in the working-age population (combined incidence of 1:3,500) These conditions display high genetic heterogeneity, with more than 200 causative genes. Proof-of-concept studies and clinical trials have recently focused on gene-specific therapeutic strategies (GSTSs),[1,2] which are successful in loss-of-function conditions.[3,4] the high genetic heterogeneity of IRDs represents a significant limitation in the development and application of GSTSs for a significant fraction of patients. Mutation-independent strategies can be used to improve the outcome of gene-specific procedures

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