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- Leclerc, D., et al.
(författare)
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Gene Editing Corrects In Vitro a G > A GLB1 Transition from a GM1 Gangliosidosis Patient
- 2023
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Ingår i: Crispr Journal. - : Mary Ann Liebert Inc. - 2573-1599 .- 2573-1602. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- 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 beta-galactosidase (beta-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 beta-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 beta-gal activity based on 3D structure bioinformatics predictions. Altogether, our results suggest that gene editing might be an alternative strategy to cure GM1 gangliosidosis.
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