Nature communications · 2024
Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia.
СтатьяResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.