Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia

Glycogen storage disease type-Ia patients, deficient in the G6PC1 gene encoding glucose-6-phosphatase-α, lack blood glucose control, resulting in life-threatening hypoglycemia. Here we show our humanized mouse model, huR83C, carrying the pathogenic G6PC1 -R83C variant displays the phenotype of glyco...

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Published inNature communications Vol. 15; no. 1; pp. 9729 - 18
Main Authors Arnaoutova, Irina, Aratyn-Schaus, Yvonne, Zhang, Lisa, Packer, Michael S., Chen, Hung-Dar, Lee, Cheol, Gautam, Sudeep, Gregoire, Francine M., Leboeuf, Dominique, Boule, Steven, Fernandez, Thomas P., Huang, Victoria, Cheng, Lo-I, Lung, Genesis, Bannister, Brianna, Decker, Jeremy, Leete, Thomas, Shuang, Lan S., Bock, Caroline, Kothiyal, Prachi, Grayson, Phil, Mok, Ka W., Quinn, Jeffrey J., Young, Lauren, Barrera, Luis, Ciaramella, Giuseppe, Mansfield, Brian C., Chou, Janice Y.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 10.11.2024
Nature Publishing Group
Nature Portfolio
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ISSN2041-1723
2041-1723
DOI10.1038/s41467-024-54108-1

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Summary:Glycogen storage disease type-Ia patients, deficient in the G6PC1 gene encoding glucose-6-phosphatase-α, lack blood glucose control, resulting in life-threatening hypoglycemia. Here we show our humanized mouse model, huR83C, carrying the pathogenic G6PC1 -R83C variant displays the phenotype of glycogen storage disease type-Ia and dies prematurely. We evaluate the efficacy of BEAM-301, a formulation of lipid nanoparticles containing a newly-engineered adenine base editor, to correct the G6PC1 -R83C variant in huR83C mice and monitor phenotypic correction through one year. BEAM-301 can correct up to ~60% of the G6PC1 -R83C variant in liver cells, restores blood glucose control, improves metabolic abnormalities of the disease, and confers long-term survival to the mice. Interestingly, just ~10% base correction is therapeutic. The durable pharmacological efficacy of base editing in huR83C mice supports the development of BEAM-301 as a potential therapeutic for homozygous and compound heterozygous glycogen storage disease type-Ia patients carrying the G6PC1 -R83C variant. In this mouse study, an adenine base editor shows potential as a durable therapy for glycogen storage disease type-Ia, correcting both the life-threatening lack of blood glucose control and metabolic abnormalities of this orphan disease.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-54108-1