RNAi Therapy Reduces Huntington's Disease Symptoms in Mouse Model

A research team used advanced gene therapy techniques to block the production of huntingtin (Htt), the toxic protein found in the brains of patients suffering from the fatal, inherited neurodegenerative disorder, Huntington's disease (HD).

Huntington’s disease is caused by a dominant gene that encodes the huntingtin protein. The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. Normal persons have a CAG repeat count of between seven and 35 repeats, while the mutated form of the gene has anywhere from 36 to 180 repeats. The mutant form of huntingtin is broken down into toxic peptides, which contribute to the pathology of the syndrome.

RNA interference (RNAi) therapy that seeks to selectively reduce the expression of Htt has emerged as a potential therapeutic strategy for this disorder. Investigators at the bio-therapeutics research company Genzyme (Framingham, MA, USA) have continued this approach by aiming to lower Htt levels and to correct the behavioral, biochemical, and neuropathological deficits shown to be associated with the YAC128 mouse model of Huntington's disease. To do this they treated these animals with a recombinant adeno-associated viral (AAV) vector that had been designed to deliver siRNA that targeted the degradation of the Htt transcript.

Results that support the continued development of AAV-mediated RNAi as a therapeutic strategy for HD were published in the May 21, 2014, issue of the journal Human Gene Therapy. They revealed that AAV-mediated RNAi was effective at transducing greater than 80% of the cells in the striatum and partially reducing the levels (by about 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.

Of particular importance was the finding that a partial reduction of both the mutant and wild-type Htt levels was not associated with any notable overt neurotoxicity.

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