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

Irina Arnaoutova, Yvonne Aratyn-Schaus, Lisa Zhang, Michael S. Packer, Hung-Dar Chen, Cheol Lee, Sudeep Gautam, Francine M. Gregoire, Dominique Leboeuf, Steven Boule, Thomas P. Fernandez, Victoria Huang, Lo-I Cheng, Genesis Lung, Brianna Bannister, Jeremy Decker, Thomas Leete, Lan S. Shuang, Caroline Bock, Prachi Kothiyal, Phil Grayson, Ka W. Mok, Jeffrey J. Quinn, Lauren Young, Luis Barrera, Giuseppe Ciaramella, Brian C. Mansfield and Janice Y. Chou ()
Additional contact information
Irina Arnaoutova: National Institutes of Health
Yvonne Aratyn-Schaus: BEAM Therapeutics
Lisa Zhang: National Institutes of Health
Michael S. Packer: BEAM Therapeutics
Hung-Dar Chen: National Institutes of Health
Cheol Lee: National Institutes of Health
Sudeep Gautam: National Institutes of Health
Francine M. Gregoire: BEAM Therapeutics
Dominique Leboeuf: BEAM Therapeutics
Steven Boule: BEAM Therapeutics
Thomas P. Fernandez: BEAM Therapeutics
Victoria Huang: BEAM Therapeutics
Lo-I Cheng: BEAM Therapeutics
Genesis Lung: BEAM Therapeutics
Brianna Bannister: BEAM Therapeutics
Jeremy Decker: BEAM Therapeutics
Thomas Leete: BEAM Therapeutics
Lan S. Shuang: BEAM Therapeutics
Caroline Bock: BEAM Therapeutics
Prachi Kothiyal: BEAM Therapeutics
Phil Grayson: BEAM Therapeutics
Ka W. Mok: BEAM Therapeutics
Jeffrey J. Quinn: BEAM Therapeutics
Lauren Young: BEAM Therapeutics
Luis Barrera: BEAM Therapeutics
Giuseppe Ciaramella: BEAM Therapeutics
Brian C. Mansfield: National Institutes of Health
Janice Y. Chou: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54108-1

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