Cas9 editing of ATXN1 in a spinocerebellar ataxia type 1 mice and human iPSC-derived neurons

Kelly J Fagan; Guillem Chillon; Ellie M Carrell; Elisa A Waxman; Beverly L Davidson

doi:10.1016/j.omtn.2024.102317

Cas9 editing of ATXN1 in a spinocerebellar ataxia type 1 mice and human iPSC-derived neurons

Mol Ther Nucleic Acids. 2024 Aug 31;35(4):102317. doi: 10.1016/j.omtn.2024.102317. eCollection 2024 Dec 10.

Authors

Kelly J Fagan^{1

2}, Guillem Chillon^{1

3}, Ellie M Carrell¹, Elisa A Waxman^{1

4}, Beverly L Davidson^{1

5

4}

Affiliations

¹ Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
² Cell and Molecular Biology Graduate Group, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, PA, USA.
³ Bioengineering Graduate Program, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Center for Epilepsy and NeuroDevelopmental Disorders (ENDD), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵ Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by an expansion of the CAG repeat region of the ATXN1 gene. Currently there are no disease-modifying treatments; however, previous work has shown the potential of gene therapy, specifically RNAi, as a potential modality. Cas9 editing offers potential for these patients but has yet to be evaluated in SCA1 models. To test this, we first characterized the number of transgenes harbored in the common B05 mouse model of SCA1. Despite having five copies of the human mutant transgene, a 20% reduction of ATXN1 improved behavior deficits without increases in inflammatory markers. Importantly, the editing approach was confirmed in induced pluripotent stem cell (iPSC) neurons derived from patients with SCA1, promoting the translatability of the approach to patients.

Keywords: ATXN1; B05 mice; CRISPR-Cas9; MT: RNA/DNA Editing; SCA1; iPSC-derived neurons; spinocerebellar ataxia.