# Examining the Role of a Pathogenic HTT Isoform, HTT1a, in Somatic Expansion and RNA Aggregation in Huntington's Disease > **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $33,780 ## Abstract PROJECT SUMMARY Huntington’s Disease (HD) is caused by expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene, resulting in transcription of mutant HTT mRNA and translation of mutant protein, both of which form nuclear aggregates in neurons. The mechanisms linking expanded CAG repeats to molecular features and outcomes of HD – including what contributes to HTT aggregation – is unclear. With the clinical failure of therapies that lower mutant HTT protein, it is crucial to better understand HD mechanisms to identify additional therapeutic targets for HD. The presence of an alternatively spliced HTT isoform, called HTT1a, is positively related to HTT CAG repeat length (predictor of HD onset), and associates with mutant HTT mRNA and protein aggregates in HD mouse models. How HTT1a and mutant HTT interact to affect aggregates, and whether this interaction can be disrupted, is unknown. It is also unclear what mechanisms favor HTT1a production. In HD patients, HTT1a is only detected in brain regions where further lengthening of the inherited HTT CAG tract had occurred over time, a process called somatic expansion. Somatic expansion, which occurs when repeats misalign after transcription, directly contributes to HD progression in mice. Whether HTT1a production is a cause or consequence of somatic expansion, and the effect of modulating this relationship on HD outcomes, has not been directly tested. This project seeks to use small interfering RNA (siRNA) to dissect the relationship between HTT1a expression, HTT aggregation, and somatic expansion in HD mouse models. siRNA scaffolds – called di-siRNA and tri-siRNA – have been optimized to enable widespread, potent gene silencing in the central nervous system (CNS) of mice. Aim 1 will determine the contribution of HTT isoforms to nuclear mRNA and protein aggregates. Delivery of di- siRNA targeting mutant HTT or HTT1a to the CNS of HD mice had no impact on aggregates, suggesting simultaneous knockdown of both transcripts may be needed to disrupt aggregation. In Aim 1, di-siRNA targeting mutant HTT, HTT1a, or both will be injected into HD mouse CNS. HTT isoform mRNA and protein expression, subcellular localization, and aggregation will be measured 1 month later. The Aim will use di-siRNA that localize to cytoplasm or nucleus to dissect the role of HTT isoforms in each subcellular compartment in aggregation. Aim 2 will dissect the relationship between somatic expansion and HTT isoform expression in HD. Somatic expansion and HTT1a are associated in HD patient brains, and co-silencing Msh3 (modifier of somatic expansion) and mutant HTT by siRNA further decreases somatic expansion compared to Msh3 silencing alone. Aim 2 will examine an interplay between somatic expansion and HTT isoforms by injecting tri-siRNA targeting Msh3, HTT isoforms, or both into HD mice, and measuring HTT isoform expression and subcellular localization, and somatic expansion 2 months later. Top siRNA that block expansion and HTT isofor... ## Key facts - **NIH application ID:** 10902689 - **Project number:** 1F31NS137681-01 - **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER - **Principal Investigator:** Sarah Jane Allen - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $33,780 - **Award type:** 1 - **Project period:** 2024-07-01 → 2027-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10902689 ## Citation > US National Institutes of Health, RePORTER application 10902689, Examining the Role of a Pathogenic HTT Isoform, HTT1a, in Somatic Expansion and RNA Aggregation in Huntington's Disease (1F31NS137681-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10902689. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*