Development of an AAV-delivered microRNA gene therapy for myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1), characterized by life-threatening muscle weakness, compromised respiration, and, often, cardiac conduction abnormalities, is the most common form of adult muscular dystrophy. DM1 is caused by a CTG repeat expansion in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene, resulting in aggregation of DMPK mRNA into insoluble ribonuclear foci that sequester RNA-binding proteins. Redistribution of essential splicing factors causes mis-splicing of factors responsible for muscle differentiation. Targeting the disease at its root by reducing DMPK RNA promises to reduce RNA foci and pathogenesis. Here, we present an adeno-associated virus (AAV)-RNAi-based strategy for DMPK reduction based on a muscle-targeted platform comprising an AAV capsid with high muscle transduction efficiency, a promoter with strong activity in muscle, and a DMPK-targeting artificial miRNA. In cellular and animal models of DM1, we show that AAV delivery of an artificial miRNA targeting DMPK reduces DMPK RNA levels and improves molecular, pathological, and clinically relevant disease hallmarks. In non-human primates, we show AAV-amiR^DMPK/SAR446268 treatment is well tolerated and results in a dose-dependent downregulation of DMPK mRNA (up to 90%) in all major muscle groups. Our data provide evidence of the efficacy and safety of SAR446268.