RNA interference as therapeutic strategy to counteract Huntington's disease

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. No cure or preventive treatments are available to date to alleviate neurodegeneration. Recent studies have demonstrated that RNAi represents a promising approach for the treatment of autosomal dominant disorders such as HD. But whether an allele-specific silencing of mutant htt or a global silencing could be considered has not previously been addressed and represents a critical issue toward clinical development. Here, we confirm the therapeutic potential of sihtt administered with lentiviral vectors and showed that initiation of siRNA treatment after the onset of HD symptoms is still efficacious and reduce the HD-like pathology in rodent. We then address the question of the impact of global silencing and demonstrated that silencing of endogenous htt to 25-35% in vivo is altering several pathways associated with known htt functions but is not inducing overt toxicity or increasing striatal vulnerability up to 9 months post-treatment. These data indicate that the coincident silencing of the wild-type and mutant htt might be considered as a therapeutic tool for HD.