# Somatic repeat expansions as a therapeutic target for trinucleotide repeat disorders

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $412,951

## Abstract

ABSTRACT
 Huntington’s disease (HD) and Friedreich ataxia (FA) are rare neurodegenerative diseases caused
by expanded trinucleotide repeats (CAG and GAA, respectively) in the HTT and FXN genes,
respectively, with larger alleles being associated with earlier disease onset and more severe clinical
phenotypes. Despite these being single gene disorders, where the respective underlying genetic
mutations have been known for over 20 years, there remains no cure or disease-modifying therapies,
indicating that novel approaches are critical. A hallmark of most repeat expansion disorders is that the
repeats are highly unstable, both intergenerationally (parent to child) and in somatic tissues, where the
repeat expands progressively over time in a cell-/tissue-specific manner. Notably, in HD, medium-spiny
neurons of the striatum, which succumb most severely to the effects of the HTT mutation, exhibit the
most dramatic CAG expansions. Similarly, larger GAA repeat expansions have been reported in the
heart and dorsal root ganglia of FA patients, where such tissues are most severely affected. These
observations, together with growing evidence from GWAS and candidate gene association studies in
HD patients, support the hypothesis that progressive repeat length increases in somatic tissues
contribute to the pathogenic process. Thus, understanding the roles of disease modifiers in somatic
repeat expansion may provide novel targets for therapeutic intervention directed at the repeat mutation
itself. To that end, we have leveraged a CRISPR-based in vivo system, recently developed by us, to
screen a number of candidate DNA repair genes and determine their role as potential modifiers of
somatic CAG repeat instability in HD. Remarkably, this has resulted in the identification of novel genes,
which when knocked out in the liver of HD mice, reduced CAG expansions and promoted contractions.
 We hereby propose a set of experiments aimed at: 1) Identifying non-invasive samples to study
CAG repeat instability as a potential biomarker of disease, as well as developing novel long-read
sequencing-based methodologies to more accurately size and quantify repeat instability; 2) Validating
candidate modifier genes in a new model of CAG expansions using HD patient-derived fibroblasts,
recently developed by us, as well as understand the potential adverse implications associated with
inactivating such DNA repair genes. We also propose to investigate if such genes are equally involved
in FA GAA expansions, using the same in vivo CRISPR platform and patient derived cellular models;
3) Development and testing of novel antisense oligonucleotide- and CRISPR-based therapeutic
approaches targeting the repeat expansion process to suppress repeat expansions or actually promote
contractions. This will lead to a better understanding of shared mechanisms across these diseases and
potentially result in novel therapeutics that can be used in all repeat expansion disorders.

## Key facts

- **NIH application ID:** 10421690
- **Project number:** 1R01NS126420-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ricardo Mouro Pinto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $412,951
- **Award type:** 1
- **Project period:** 2022-04-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10421690

## Citation

> US National Institutes of Health, RePORTER application 10421690, Somatic repeat expansions as a therapeutic target for trinucleotide repeat disorders (1R01NS126420-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10421690. Licensed CC0.

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