Gene editing is suitable to treat GM1 Gangliosidosis: a proof-of-concept study

Leclerc, D.; Goujon, L.; Jaillard, S.; Nouyou, B.; Cluzeau, L.; Damaj, L.; Dubourg, C.; Etcheverry, A.; Levade, T.; Froissart, R.; Dreano, S.; Guillory, X.; Eriksson, L. A.; Launay, E.; Mouriaux, F.; Belaud-Rotureau, M.-A.; Odent, S.; Gilot, D.

doi:10.1101/2022.04.17.488473

bioRxiv · 10.1101/2022.04.17.488473

Gene editing is suitable to treat GM1 Gangliosidosis: a proof-of-concept study

Leclerc, D.·Goujon, L.·Jaillard, S.·Nouyou, B.·Cluzeau, L.·Damaj, L.·Dubourg, C.·Etcheverry, A.·Levade, T.·Froissart, R.·Dreano, S.·Guillory, X.·Eriksson, L. A.·Launay, E.·Mouriaux, F.·Belaud-Rotureau, M.-A.·Odent, S.·Gilot, D.

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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. Here, we show that 41% of GLB1 pathogenic SNVs might be cured by adenine base editors (ABEs). Our results demonstrate that ABE efficiently corrects the pathogenic allele in patient-derived fibroblasts, restoring a therapeutic level of {beta}-gal activity. Unbiased off-target DNA analysis did not detect off-target editing activity in treated patients cells except a bystander edit without consequences on {beta}-gal activity. Altogether our results suggest that gene editing is an alternative strategy to cure GM1 gangliosidosis, by correcting the root cause of disease and avoiding repetitive adeno-associated virus injections.

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Leclerc, D., Goujon, L., Jaillard, S., Nouyou, B., Cluzeau, L., Damaj, L., Dubourg, C., Etcheverry, A., Levade, T., Froissart, R., Dreano, S., Guillory, X., Eriksson, L. A., Launay, E., Mouriaux, F., Belaud-Rotureau, M.-A., Odent, S., Gilot, D.. 2022-04-17. Gene editing is suitable to treat GM1 Gangliosidosis: a proof-of-concept study. https://doi.org/10.1101/2022.04.17.488473

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