ERA-Net E-Rare

Polyglutamine (polyQ) diseases are a group of monogenic, autosomal dominant neurodegenerative disorders caused by a polyQ encoding CAG triplet repeat expansion in the disease causing gene with pathogenic consequences. The most prevalent polyQ disorders are Huntington disease (HD) and spinocerebellar ataxia type 3 (SCA3), while spinocerebellar ataxia type 7 (SCA7) shows some unique features for development of therapeutics. All three diseases begin in young adults, cause severe disability and lead to premature death. Currently, there is a complete lack of disease modifying treatment for any of these disorders. Targeting specific mechanisms that are thought to be relevant to human disease pathogenesis is very challenging as the disease genes are often pleiotropic and there is only scant data from human studies to prioritize biological mechanisms. Our project bridges these challenges by specifically targeting the causative mutant gene or its transcript and testing for efficacy of three promising gene-suppressive strategies: ASO, RNAi and CRISPR/Cas9, in multiple unique and suitable model systems. Specifically, we will 1) use population genetics to identify targets of greatest therapeutic potential to design novel gene silencing molecules for these targets, 2) evaluate the efficacy of novel, optimized ASOs, RNAis and sgRNAs in in vitro and in vivo models, 3) develop potential biomarkers of brain target protein levels and 4) apply novel MRI / NMR methods as potential imaging biomarkers for disease progression and evaluating therapeutic efficacy.