# Huntington's Disease Repeat Instability and Pathogenesis

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $668,849

## Abstract

ABSTRACT
Huntington’s disease (HD) is a devastating and fatal neurodegenerative disorder caused by the expansion of a
polymorphic CAG repeat in the HTT gene that triggers cell death with specificity towards neurons in the
striatum and cortex. Although the underlying genetic mutation was discovered over 25 years ago, there is still
no cure or effective treatment despite extensive efforts. The HTT CAG repeat mutation is highly unstable both
in transmissions to subsequent generations and somatically. Notably the repeat undergoes dramatic tissue-
specific somatic expansion, particularly in the brain regions affected in the disorder, strongly suggesting that
somatic HTT CAG length increases in target tissues contribute to HD pathogenesis. Recent human genetic
data provide compelling support for somatic CAG expansion as a driver of the rate of HD pathogenesis,
identifying DNA repair genes as modifiers of disease onset in HD patients, many of which modify somatic CAG
expansion in accurate genetic HD knock-in mouse models. In this study, we will perform experiments to deeply
interrogate these modifier genes at a number of fundamental levels. In Aim 1 we will use genetic experiments
in the mouse to test the impact of altering somatic expansion on disease expression. In Aim 2, we will perform
biochemical studies in patient cells and in mouse models to understand the mechanism of action and
functional consequences a human modifier variant. In Aim 3 we will examine the impacts of human modifier
variation on CAG instability and gene expression in specific cell types in the brain. Together, these
experiments that are driven by human genetic data, will provide critical insight into mechanisms of disease
modification in HD and will guide development of therapeutics targeting CAG expansion.

## Key facts

- **NIH application ID:** 10833714
- **Project number:** 5R01NS049206-18
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** VANESSA C WHEELER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $668,849
- **Award type:** 5
- **Project period:** 2005-09-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833714

## Citation

> US National Institutes of Health, RePORTER application 10833714, Huntington's Disease Repeat Instability and Pathogenesis (5R01NS049206-18). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10833714. Licensed CC0.

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