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

Delphine Leclerc (1) , Louise Goujon (2) , Sylvie Jaillard (3, 4, 2) , Bénédicte Nouyou (2) , Laurence Cluzeau (2) , Lena Damaj (2) , Christèle Dubourg (5) , Amandine Etcheverry (2) , Thierry Levade (6) , Roseline Froissart (7) , Stéphane Dreano (5) , Xavier Guillory (1, 8) , Leif A. Eriksson (9) , Erika Launay (2) , F Mouriaux (1, 2) , Marc-Antoine Belaud-Rotureau (3, 4, 2) , Sylvie Odent (2, 5) , David Gilot (1, 2)

1 OSS - Oncogenesis, Stress, Signaling
2 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
3 EHESP - École des Hautes Études en Santé Publique [EHESP]
4 Irset - Institut de recherche en santé, environnement et travail
5 IGDR - Institut de Génétique et Développement de Rennes
6 Institut Fédératif de Biologie (IFB)
7 HCL - Hospices Civils de Lyon
8 ISCR - Institut des Sciences Chimiques de Rennes
9 GU - Göteborgs Universitet = University of Gothenburg

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]

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⟩