CRISPR‐based therapeutic and modelling approaches in Huntington's disease: Progress, challenges and future directions
TL;DR
No approach yet combines adequate central nervous system distribution, mutant‐allele selectivity, durable neurological benefit, and established long‐term safety in 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.
Abstract
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. To evaluate CRISPR technologies for HTT modulation, validation of somatic CAG‐expansion modifiers, and HD modeling, with emphasis on efficacy, selectivity, delivery, and safety. 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. 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. 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.
