Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice

Matuszek, Z., Arbab, M., Kesavan, M. et al. Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice. Nat Genet (2025). doi:10.1038/s41588-025-02172-8 

 In this study, we have begun the characterization of unintended targets of these repeat base editing strategies, and found that: (1) the level of off-target editing is inversely correlated with the number of mismatches between the repeat-targeting sgRNA and the sequence of the off-target locus, as expected70,71,72; (2) the vast majority of undesired editing occurs in noncoding or intergenic regions of the human genome; and (3) repeat-targeting base editing often leads to the induction of benign single-nucleotide variations that are observed in the general population and synonymous substitutions at protein-coding loci that preserve endogenous protein sequence. The alternative target and off-target sites of repeat-targeting in the human genome observed in this study warrant further comprehensive cell-type-specific longitudinal analyses to evaluate the regulatory risks of accumulated mutations in targeted tissues, to better assess the safety profile of our approaches and whether interrupting pathogenic repeats that underlie TNR diseases may be a viable therapeutic approach in the future. Nonetheless, the approaches and findings developed here should prove useful to elucidate the causality and biological consequences of uninterrupted and interrupted repeat tracts in cultured cells and animal models of TNR diseases.

Impaired DNA double-strand breaks repair in Friedreich’s Ataxia fibroblasts

Rafka Challita, Dana Tohme, Charbel Feghaly, Hanin Bou Hadir, Walaa Chebli, Elie Estephan, Rana El-Hassan, Sima Hussayni, Wassim Abou Kheir, Larry Bodgi, 2735 Impaired DNA double-strand breaks repair in Friedreich’s Ataxia fibroblasts, Radiotherapy and Oncology, Volume 206, Supplement 1, 2025, Pages S3933-S3935, ISSN 0167-8140, doi:10.1016/S0167-8140(25)01252-6.

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