bioRxiv : the preprint server for biologyJan 9, 2026

Using a CRISPR tool that targets all forms of the huntingtin protein to treat Huntington's disease

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A pan-HTT CRISPR-Cas9 approach lowered huntingtin and improved Huntington's disease-like phenotypes in mouse models.

Evidence

This was a preclinical AAV5-delivered CRISPR-Cas9 study in R6/2, YAC128, and Hu21/21 mice, showing 55-80% mutant HTT mRNA and protein lowering in HD models and 44% HTT protein lowering in Hu21/21 mice.

Caveat

The work remains mouse-model evidence, and HTT targeting in Hu21/21 mice was associated with neuroinflammation despite no measurable behavioral deficits or neuronal viability loss.

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 provides insights into its tolerability.

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CRISPR Gene EditingIssue #19

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Using a CRISPR tool that targets all forms of the huntingtin protein to treat Huntington's disease

Abstract

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