Lowering theHTT1atranscript as an effective therapy for Huntington’s disease

Lowering the levels ofHTTtranscripts 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 theHTTgene, and the rate of somatic expansion of this CAG repeat throughout life is now known to drive the age of onset and rate of disease progression. As the CAG repeat expands, the extent to which theHTTmRNA is alternatively processed to generate theHTT1atranscript and highly aggregation-prone and pathogenic HTT1a protein increases. Several HTT-lowering modalities have entered clinical trials that either target bothHTTandHTT1atogether, or full-lengthHTTalone. We have developed siRNAs that target theHtt1amouse transcript (634/486) and used these, together with a potentHtt-targeting siRNA (10150) to compare the efficacy of lowering either full-lengthHttorHtt1a. zQ175 and wild-type mice were treated with 10150 or 634/486 alongside control groups at 2 months of age with treatment to 6 or 10 months, or at 6 months with treatment to 10 months. The siRNA potency and durability were most effective in the hippocampus. Whilst both strategies showed benefits, despite the greater potency of 10150, targetingHtt1awas more effective at delaying HTT aggregation and transcriptional dysregulation than targeting full-lengthHtt. These data support HTT-lowering strategies that are designed to target theHTT1atranscript, either alone, or together with lowering full-lengthHTT.