Lowering the HTT1a transcript as an effective therapy for Huntington's disease in a knockin mouse model.

Lowering huntingtin (HTT) transcript levels has been a major focus of therapeutic development for Huntington's disease (HD), but which transcript should be lowered? HD is caused by a CAG repeat expansion in exon 1 of the HTT gene, and the rate of somatic expansion of this CAG repeat throughout life drives the age of onset and rate of disease progression. As the CAG repeat expands, the extent to which the HTT mRNA is alternatively processed to generate the HTT1a transcript and highly aggregation-prone and pathogenic HTT1a protein increases. Several HTT-lowering modalities have entered clinical trials that target either both HTT and HTT1a together or full-length HTT alone. We have developed siRNAs that target the Htt1a mouse transcript (634/486) and used these, together with a potent Htt-targeting siRNA (10150), to compare the efficacy of lowering either full-length Htt or Htt1a. zQ175 and wild-type mice were treated with 10150 or 634/486 alongside control groups at 2 months of age and euthanized at 6 months, at 2 months and again at 6 months and euthanized at 10 months, or at 6 months and euthanized at 10 months. The siRNA potency and durability were most effective in the hippocampus. Although both strategies showed benefits, despite the greater potency of 10150, targeting Htt1a was more effective at delaying HTT aggregation and transcriptional dysregulation than targeting full-length Htt. These data support HTT-lowering strategies that are designed to target the HTT1a transcript, either alone or together with lowering full-length HTT.