Lowering the HTT1a transcript as an effective therapy for Huntingtons disease

Papadopoulou, A. S.; Alterman, J.; Landles, C.; Smith, E. J.; Conroy, F.; Phillips, J.; Canibano-Pico, M.; Nita, I. M.; Osborne, G. F.; Iqbal, A.; Aldous, S. G.; Bondulich, M. K.; Gomez-Paredes, C.; Sathasivam, K.; O'Reilly, D.; Echeverria, D.; Bobkov, K.; Greene, J. R.; Aronin, N.; Khvorova, A.; Bates, G. P.

doi:10.1101/2025.06.10.658804

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bioRxiv · 10.1101/2025.06.10.658804

Lowering the HTT1a transcript as an effective therapy for Huntingtons disease

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Abstract

Lowering the levels of HTT transcripts has been a major focus of therapeutic development for Huntingtons 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 is now known to drive 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 either target 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 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, 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. One Sentence SummaryLowering HTT1a transcript levels delays the onset of molecular and neuropathological phenotypes in a knock-in mouse model of Huntingtons disease.

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Papadopoulou, A. S., Alterman, J., Landles, C., Smith, E. J., Conroy, F., Phillips, J., Canibano-Pico, M., Nita, I. M., Osborne, G. F., Iqbal, A., Aldous, S. G., Bondulich, M. K., Gomez-Paredes, C., Sathasivam, K., O'Reilly, D., Echeverria, D., Bobkov, K., Greene, J. R., Aronin, N., Khvorova, A., Bates, G. P.. 2025-06-11. Lowering the HTT1a transcript as an effective therapy for Huntingtons disease. https://doi.org/10.1101/2025.06.10.658804

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