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 in | Nature communications Vol. 15; no. 1; pp. 9729 - 18 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
10.11.2024
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
ISSN | 2041-1723 2041-1723 |
DOI | 10.1038/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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-024-54108-1 |