# Selective Editing of the Mutant Huntingtin Gene

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $465,305

## Abstract

The cause of Huntington’s disease is an increase in the trinucleotide CAG repeat from under 36
repeats to 36 or greater repeats. The mode for the number of repeats is 42, and most patients have between
40 and 45. The disease generally starts between ages 30 and 40, with onset and progression of impaired
cognition, depression, and aberrant movement. The genetics is autosomal dominant. With gene editing, we
aim to eliminate expression of the mutant allele of Huntington’s disease or repair the mutation by reducing the
number of CAG repeats. We will use CRISPR-Cas9 for selective targeting of single nucleotide polymorphisms
with heterozygosities to prevent the mutant huntingtin allele from producing protein. Generating frameshift
mutations at the SNP heterozygosity reduces mutant huntingtin protein, with no production of mutant protein
fragments. In a second approach, we reduce the number of CAG repeats from a high number in the mutant
allele to a healthy number of CAG repeats, through the use of Cas9 nickases. The nickase Cas9D10A is used to
reduce the CAG repeat number below the pathogenic threshold. We have preliminary data that supports each
aspect of the proposal. The goal of this discovery application is to set the stage for promising therapeutics for
treatment of Huntington’s disease and other autosomal dominant neurological disorders caused by
trinucleotide CAG repeat expansions.

## Key facts

- **NIH application ID:** 10139111
- **Project number:** 5R01NS106245-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** NEIL ARONIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $465,305
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10139111

## Citation

> US National Institutes of Health, RePORTER application 10139111, Selective Editing of the Mutant Huntingtin Gene (5R01NS106245-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10139111. Licensed CC0.

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