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

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 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.

• Authors: Delphine Leclerc, Louise Goujon, Sylvie Jaillard, Bénédicte Nouyou, Laurence Cluzeau, Léna Damaj, Christèle Dubourg, Amandine Etcheverry, Thierry Levade, Roseline Froissart, Stéphane Dréano, Xavier Guillory, Leif A Eriksson, Erika Launay, Frédéric Mouriaux, Marc-Antoine Belaud-Rotureau, Sylvie Odent, David Gilot
• Journal: The CRISPR journal (CRISPR J) Vol. 6 Issue 1 Pg. 17-31 (02 2023) ISSN: 2573-1602 [Electronic] United States
• PMID: 36629845 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• beta-Galactosidase
• GLB1 protein, human

Topics

• Humans
• Gangliosidosis, GM1 (therapy, drug therapy)
• beta-Galactosidase (genetics, chemistry, metabolism)
• Gene Editing
• CRISPR-Cas Systems (genetics)
• Alleles