Gene Editing Corrects In Vitro a G > A GLB1 Transition from a GM1 Gangliosidosis Patient - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue The Crispr Journal Année : 2023

Gene Editing Corrects In Vitro a G > A GLB1 Transition from a GM1 Gangliosidosis Patient

Thierry Levade
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Roseline Froissart
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Résumé

Ganglioside-monosialic acid (GM1) gangliosidosis, a rare autosomal recessive disorder, is frequently caused by deleterious single nucleotide variants (SNVs) in GLB1 gene. These variants result in reduced β-galactosidase (β-gal) activity, leading to neurodegeneration associated with premature death. Currently, no effective therapy for GM1 gangliosidosis is available. Three ongoing clinical trials aim to deliver a functional copy of the GLB1 gene to stop disease progression. In this study, we show that 41% of GLB1 pathogenic SNVs can be replaced by adenine base editors (ABEs). Our results demonstrate that ABE efficiently corrects the pathogenic allele in patient-derived fibroblasts, restoring therapeutic levels of β-gal activity. Off-target DNA analysis did not detect off-target editing activity in treated patient’s cells, except a bystander edit without consequences on β-gal activity based on 3D structure bioinformatics predictions. Altogether, our results suggest that gene editing might be an alternative strategy to cure GM1 gangliosidosis.

Dates et versions

hal-03968195 , version 1 (01-02-2023)

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Citer

Delphine Leclerc, Louise Goujon, Sylvie Jaillard, Bénédicte Nouyou, Laurence Cluzeau, et al.. Gene Editing Corrects In Vitro a G > A GLB1 Transition from a GM1 Gangliosidosis Patient. The Crispr Journal, 2023, 6 (1), pp.17-31. ⟨10.1089/crispr.2022.0045⟩. ⟨hal-03968195⟩
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