CRISPR‐based therapeutic and modelling approaches in Huntington's disease: Progress, challenges and future directions
11 affiliations
- 1Department of Organization, Management and Economics of Pharmacy and Clinical Pharmacy Asfendiyarov Kazakh National Medical University Almaty Kazakhstan
- 2Department of Histology, Cytology and Embryology Samarkand State Medical University Samarkand Uzbekistan
- 3Department of Surgical Dentistry Bukhara State Medical Institute Named After Abu Ali ibn Sino Bukhara Uzbekistan
- 4Department of Family Medicine No. 2 and Clinical Pharmacology Tashkent State Medical University Tashkent Uzbekistan
- 5Department of General Surgery No. 3 Tashkent State Medical University Tashkent Uzbekistan
- 6Department of General Surgery, Topographic Anatomy and Operative Surgery No. 3 Tashkent State Medical University Tashkent Uzbekistan
- 7Department of Normal Physiology Andijan State Medical Institute Andijan Uzbekistan
- 8Department of General Surgery Fergana Medical Institute of Public Health Fergana Uzbekistan
- 9Department of Sports Theory Termez State University Termez Uzbekistan
- 10Clinical Research Development Center Shahid Modarres Educational Hospital, Shahid Beheshti University of Medical Sciences Tehran Iran
- 11Department of Mycobacteriology and Pulmonary Research Pasteur Institute of Iran Tehran Iran
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.
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BibTeX
@article{zhakipbekov2026crisprbased,
title = {{CRISPR‐based therapeutic and modelling approaches in Huntington's disease: Progress, challenges and future directions}},
author = {Kairat Zhakipbekov and Surayyo Eshkabilova and Zokir Raximov and Sharof Eshonov and Abdusaid Khasanov and Ziyodulla Tokhtamurod and Axmadjan Ashurmetov and Avazbek Abduraxmanov and Niyozbek Abdurakhmonov and Elmurod Eshqobilov and Seyed Mohsen Mirhosseini and Amir Arsalan Ghahari},
journal = {Clinical and Translational Discovery},
year = {2026},
month = oct,
doi = {10.1002/ctd2.70211},
url = {https://doi.org/10.1002/ctd2.70211},
note = {CC BY},
}
RIS
TY - JOUR
TI - CRISPR‐based therapeutic and modelling approaches in Huntington's disease: Progress, challenges and future directions
AU - Kairat Zhakipbekov
AU - Surayyo Eshkabilova
AU - Zokir Raximov
AU - Sharof Eshonov
AU - Abdusaid Khasanov
AU - Ziyodulla Tokhtamurod
AU - Axmadjan Ashurmetov
AU - Avazbek Abduraxmanov
AU - Niyozbek Abdurakhmonov
AU - Elmurod Eshqobilov
AU - Seyed Mohsen Mirhosseini
AU - Amir Arsalan Ghahari
PY - 2026
DA - 2026/10/26
JO - Clinical and Translational Discovery
DO - 10.1002/ctd2.70211
UR - https://doi.org/10.1002/ctd2.70211
AB - 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.
SN - 2768-0622
ER -