Symptomatic mice AAV9 U1fd-treated

Familial dysautonomia (FD) is a rare genetic disease with no treatment, caused by a splicing mutation (c.2204+6T>C) that induces exon 20 skipping in the elongator complex protein 1 gene (ELP1). Here, we evaluated the therapeutic potential of a novel class of U1 snRNA molecules, exon-specific U1s (ExSpeU1s) in a symptomatic FD mouse model characterized by degeneration of the sensory and autonomic nervous system. Postnatal intraperitoneal and intra cerebroventricular delivery of FD-ExSpeU1s-adeno-associated virus (AAV9-U1-Fd) particles increased the ELP1 exon 20 inclusion and ELP1 protein production in several tissues including Brain, Dorsal Root and Trigeminal Ganglia rescuing most of the FD mouse mortality that occurs by 3 months of age (75% vs 40%). Treated mice recovered the neuromuscular functions, cardiac output and serum creatinine levels. Overexpressing Fd-ExspeU1 in human cells and in Dorsal Root Ganglia did not significantly alter global gene expression and showed only negligible off target effects on splicing. Our data provide therapeutic and safety profile of Fd-ExSpeU1s-adeno-associated virus particles as an effective therapeutic strategy for FD.