CRISPR-based therapeutic and modelling approaches in Huntington's disease: Progress, challenges and future directions

Abstract

Background

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG-repeat expansion in exon 1 of the huntingtin gene (HTT). Mutant huntingtin accumulation and somatic repeat expansion contribute to neuronal dysfunction, making HD a compelling target for CRISPR-based intervention.

Objective

To evaluate CRISPR technologies for HTT modulation, validation of somatic CAG-expansion modifiers, and HD modeling, with emphasis on efficacy, selectivity, delivery, and safety.

Methods

This narrative review synthesizes preclinical evidence on DNA-targeting nucleases, CRISPR interference, RNA-targeting Cas13 systems, repeat stabilization, functional screens, and cellular and animal models. Approaches are compared by mechanism, durability, allele selectivity, central nervous system delivery, and translational limitations.

Results

Cas9-based strategies can disrupt HTT or excise exon 1, while SNP-linked PAMs and guide mismatches may enable allele-selective editing in genetically eligible patients. dCas9-KRAB represses HTT transcription without DNA cleavage, whereas RfxCas13d/CasRx reduces HTT RNA without permanent genome modification; for both, selectivity and durability depend on guide design and delivery. CRISPR screens have identified expansion-promoting DNA repair factors, including MSH3, MLH3, and PMS1, whereas protective factors such as FAN1 should be preserved. CAG-to-CAA base editing offers a complementary repeat-stabilizing strategy. CRISPR-corrected isogenic induced pluripotent stem cell-derived neurons, organoids, and CRISPR-generated large-animal models strengthen mechanistic studies; conventional Q140 and zQ175 knock-in mice remain useful for testing interventions but were not generated using CRISPR. Evidence remains preclinical. Major barriers include brain-wide delivery, incomplete neuronal coverage, loss of wild-type HTT function, heterogeneous on-target repair, off-target DNA or RNA activity, immune responses, durability, patient stratification, and long-term safety.

Conclusions

CRISPR is a versatile platform for HD research and development, but no approach yet combines adequate central nervous system distribution, mutant-allele selectivity, durable neurological benefit, and established long-term safety. Clinical translation requires comparative studies, allele-resolved and genome-wide safety assessment, validated delivery systems and biomarkers, and long-term evaluation in disease-relevant models.