Silencing mutant huntingtin by AAV-mediated RNAi ameliorates disease manifestations in the YAC128 mouse model of Huntington's disease.

Human gene therapy

PubMedID: 24484067

Stanek LM, Sardi SP, Mastis B, Richards AR, Treleaven CM, Taksir T, Misra K, Cheng SH, Shihabuddin LS. Silencing mutant huntingtin by AAV-mediated RNAi ameliorates disease manifestations in the YAC128 mouse model of Huntington's disease. Hum Gene Ther. 2014;.
Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease caused by an increase in the number of polyglutamine residues in the huntingtin (Htt) protein. With the identification of the underlying basis of HD, therapies are being developed that reduce the expression of the causative mutant Htt. RNA interference (RNAi) that seeks to selectively reduce the expression of such disease-causing agents is emerging as a potential therapeutic strategy for this and similar disorders. This study examined the merits of administering a recombinant adeno-associated viral (AAV) vector designed to deliver siRNA that targets the degradation of the Htt transcript. The aim was to lower Htt levels and to correct the behavioral, biochemical, and neuropathological deficits shown associated with the YAC128 mouse model of HD. Our data demonstrated that AAV-mediated RNAi was effective at transducing greater than 80 percent of the cells in the striatum and partially reducing the levels (~40%) of both wild-type and mutant Htt in this region. Concomitant with these reductions were significant improvements in behavioral deficits, reduction of striatal Htt aggregates, and partial correction of the aberrant striatal transcriptional profile observed in YAC128 mice. Importantly, a partial reduction of both the mutant and wild-type Htt levels was not associated with any notable overt neurotoxicity. Collectively, these results support the continual development of AAV-mediated RNAi as a therapeutic strategy for HD.