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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene.
• Somatic expansion of this CAG repeat influences disease onset and progression.
• Increased CAG repeats lead to alternative splicing, generating the pathogenic HTT1a transcript and protein.

Purpose of the Study:

• To compare the efficacy of lowering full-length huntingtin (HTT) versus the HTT1a transcript in mouse models of HD.
• To evaluate siRNA strategies targeting either HTT or HTT1a for therapeutic potential.

Main Methods:

• Development of siRNAs targeting mouse Htt1a (634/486) and Htt (10150).
• Treatment of zQ175 (HD model) and wild-type mice with siRNAs at different ages.
• Assessment of siRNA efficacy, potency, and durability, particularly in the hippocampus.

Main Results:

• Both HTT-lowering strategies demonstrated therapeutic benefits in HD mouse models.
• Targeting HTT1a was more effective than targeting full-length HTT in reducing HTT aggregation and transcriptional dysregulation.
• siRNA potency and durability were most pronounced in the hippocampus.

Conclusions:

• HTT-lowering strategies targeting the HTT1a transcript show greater efficacy in mitigating HD pathology.
• These findings support the development of therapies focused on HTT1a, alone or in combination with full-length HTT lowering.