Gene Editing Corrects In Vitro a G > A GLB1 Transition from a GM1 Gangliosidosis Patient
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.
Domaines
Sciences du Vivant [q-bio]
Fichier principal
Gene_Editing_Corrects_In_Vitro_a_G_A_GLB1_Transiti.pdf (1.06 Mo)
Télécharger le fichier
PMC9986017.html (230.86 Ko)
Télécharger le fichier
| Origine | Publication financée par une institution |
|---|
| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
|---|