In vivo CRISPR base editing for treatment of Huntington’s disease
11 affiliations
- 1Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA
- 2Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA
- 3Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA
- 4Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL, USA
- 5Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected]
- 6Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected]
- 7Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected]
- 8Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected]
- 9Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected]
- 10Department of Biomedical and Translational Science, The Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected]
- 11Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected]
Abstract
Huntington's disease (HD) is an inherited and ultimately fatal neurodegenerative disorder caused by an expanded polyglutamine-encoding CAG repeat within exon 1 of the huntingtin (HTT) gene, which produces a mutant protein that destroys striatal and cortical neurons. Importantly, a critical event in the pathogenesis of HD is the proteolytic cleavage of the mutant HTT protein by caspase-6, which generates fragments of the N-terminal domain of the protein that form highly toxic aggregates. Given the role that proteolysis of the mutant HTT protein plays in HD, strategies for preventing this process hold potential for treating the disorder. By screening 141 CRISPR base editor variants targeting splice elements in the HTT gene, we identified platforms capable of producing HTT protein isoforms resistant to caspase-6-mediated proteolysis via editing of the splice acceptor sequence for exon 13. When delivered to the striatum of a rodent HD model, these base editors induced efficient exon skipping and decreased the formation of the N-terminal fragments, which in turn reduced HTT protein aggregation and attenuated striatal and cortical atrophy. Collectively, these results illustrate the potential for CRISPR base editing to decrease the toxicity of the mutant HTT protein for HD.
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BibTeX
@article{shirguppe2026vivo,
title = {{In vivo CRISPR base editing for treatment of Huntington’s disease}},
author = {Shraddha Shirguppe and Michael Gapinske and Devyani Swami and Kyrollos Shenouda and Angelo Miskalis and Nicholas C. Gosstola and Daniela Del Bosque Siller and Isabelle Guerra and Pankaj Acharya and Dana Joulani and Maddie G. Szkwarek and Ananthan Nambiar and Abhishek Bhattacharjee and Anagha S. Dangi and Norah Odle and Gabrielle E. Nathan and Gianna Elias and Michelle Stilger and Jackson Winter and Wendy S. Woods and Daphine Anand and Colin K.W. Lim and Sergei Maslov and Thomas Gaj and Pablo Pérez‐Piñera},
journal = {Nature Biomedical Engineering},
year = {2026},
month = jul,
doi = {10.1038/s41551-026-01747-y},
url = {https://doi.org/10.1038/s41551-026-01747-y},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - In vivo CRISPR base editing for treatment of Huntington’s disease
AU - Shraddha Shirguppe
AU - Michael Gapinske
AU - Devyani Swami
AU - Kyrollos Shenouda
AU - Angelo Miskalis
AU - Nicholas C. Gosstola
AU - Daniela Del Bosque Siller
AU - Isabelle Guerra
AU - Pankaj Acharya
AU - Dana Joulani
AU - Maddie G. Szkwarek
AU - Ananthan Nambiar
AU - Abhishek Bhattacharjee
AU - Anagha S. Dangi
AU - Norah Odle
AU - Gabrielle E. Nathan
AU - Gianna Elias
AU - Michelle Stilger
AU - Jackson Winter
AU - Wendy S. Woods
AU - Daphine Anand
AU - Colin K.W. Lim
AU - Sergei Maslov
AU - Thomas Gaj
AU - Pablo Pérez‐Piñera
PY - 2026
DA - 2026/07/29
JO - Nature Biomedical Engineering
DO - 10.1038/s41551-026-01747-y
UR - https://doi.org/10.1038/s41551-026-01747-y
AB - Huntington's disease (HD) is an inherited and ultimately fatal neurodegenerative disorder caused by an expanded polyglutamine-encoding CAG repeat within exon 1 of the huntingtin (HTT) gene, which produces a mutant protein that destroys striatal and cortical neurons. Importantly, a critical event in the pathogenesis of HD is the proteolytic cleavage of the mutant HTT protein by caspase-6, which generates fragments of the N-terminal domain of the protein that form highly toxic aggregates. Given the role that proteolysis of the mutant HTT protein plays in HD, strategies for preventing this process hold potential for treating the disorder. By screening 141 CRISPR base editor variants targeting splice elements in the HTT gene, we identified platforms capable of producing HTT protein isoforms resistant to caspase-6-mediated proteolysis via editing of the splice acceptor sequence for exon 13. When delivered to the striatum of a rodent HD model, these base editors induced efficient exon skipping and decreased the formation of the N-terminal fragments, which in turn reduced HTT protein aggregation and attenuated striatal and cortical atrophy. Collectively, these results illustrate the potential for CRISPR base editing to decrease the toxicity of the mutant HTT protein for HD.
SN - 2157-846X
ER -