Molecular therapy : the journal of the American Society of Gene TherapyApr 26, 2026

Using CRISPR to treat Huntington's disease by targeting all forms of the huntingtin protein

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 27, 2026

Abstract

A pan-HTT-targeting CRISPR-Cas9 system reduced mutant HTT mRNA and protein by 55-80% in mouse models of Huntington's disease.

Induction of frameshift mutations in the HTT gene led to significant decreases in mutant protein levels.
Improved motor coordination and locomotor activity were observed in R6/2 and YAC128 mice, alongside reduced anxiety-like behaviors.
The treatment resulted in decreased clasping behavior, weight loss, and striatal atrophy.
In Hu21/21 mice, Cas9 lowered HTT protein levels by 44% without causing behavioral deficits or negatively impacting neuronal viability.
However, Cas9 targeting was associated with neuroinflammation.

Simplified

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene, which leads to a mutant protein that destroys neurons in the brain. Despite intense effort, there remains no approved disease-modifying therapy for HD. Here we develop a pan-HTT-targeting CRISPR-Cas9 system that, when delivered to the striatum of R6/2 and YAC128 mice by AAV5, lowered mutant HTT mRNA and protein by 55-80% via its induction of frameshift-inducing indel mutations in HTT exon 1. Cas9 targeting improved motor coordination and locomotor activity, decreased anxiety-like deficits, reduced clasping and weight loss, limited striatal atrophy, and decreased the formation of intranuclear inclusions immunoreactive for the mutant HTT protein. In Hu21/21 mice, which carry the wild-type human HTT gene in lieu of the mouse ortholog, Cas9 lowered the HTT protein by 44% but induced no measurable behavioral deficits and had no adverse effect on neuronal viability, though its targeting was associated with neuroinflammation. Altogether, our results demonstrate the ability for a newly developed pan-HTT-targeting Cas9 system to affect HD-related phenotypes across models and provide insights into its tolerability.

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Funding

Competing interests

Declaration of interests This work was supported by a sponsored research agreement with Sarepta Therapeutics. T.G. is a member of the Editorial Board for Molecular Therapy. M.R.H. is the Chief Executive Officer of Prilenia Therapeutics and serves on the public boards of Ionis Pharmaceuticals, AbCellera, and 89bio.

PubMed

Using CRISPR to treat Huntington's disease by targeting all forms of the huntingtin protein

Abstract

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Funding

Competing interests

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Abstract

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