THERADM

Myotonic Dystrophy type 1 (DM1) is an autosomal dominant disease caused by the expression of toxic RNAs containing expanded CUG repeats. These pathogenic RNAs are retained in the nucleus as riboprotein aggregates that sequester MBNL splicing factors leading to alternative splicing misregulations associated with clinical symptoms. We engineered a modified MBNL? polypeptide that is able to target expanded CUG repeats in order to displace endogenous sequestered MBNL proteins from CUG-RNA nuclear aggregates and restores their cellular functions. Expression of MBNL? results in correction of alternative splicing defects in DM1 models both in vitro and in vivo. Moreover myotonia, a hallmark of DM1 disease affecting skeletal muscles is also abolished. Our project is to develop an optimized MBNL? tool, decipher its mechanism of action, bring fundamental knowledge about MBNL contribution in DM1 pathogenesis and assess its use in a new decoy-based gene therapy approach. AAV vectors will be used to deliver MBNL? in DM1 mouse models, and molecular as well as physiological effects of local (brain, heart, muscle) but also systemic MBNL? delivery will be assessed in tissues that are severely affected in DM1 patients. Our project will position this innovative MBNL? tool as an alternate or complementary therapeutic approach to counteract the degenerative processes taking place in this multisystemic disease.