Evaluating Gene Editing to Treat a Rare Disease

Model of the glucose molecule.

People with the rare hereditary disorder glycogen storage disease type Ia (GSD-Ia) cannot maintain blood sugar levels. Thus, they experience seizures, growth problems, and other issues. GSD-Ia is caused by G6PC1 gene variations that cause defects in glucose-6-phosphatase alpha, an enzyme found in the liver and kidneys that produces the sugar glucose from glycogen and other sources. Although researchers have previously tried to compensate for the loss of function of the G6PC1 gene, their findings have limitations.

The Chou Lab and colleagues at NICHD and BEAM Therapeutics used a CRISPR-based gene editing approach that exchanges a single DNA base pair for another DNA base pair. They tested the treatment, called BEAM-301, in a mouse model they developed that has the human version of the variant G6PC1 gene. The DNA base editing technology was contained in lipid nanoparticles (tiny structures made of fatty material) injected into the animals’ bloodstream and absorbed by the liver, where they were taken into liver cells.
The therapy corrected the variant genes in up to 60% of the animals’ liver cells, restoring the ability to produce glucose from glycogen and other sources. Older editing techniques corrected the variant in less than 2% of the animals’ cells.
Animals treated with BEAM-301 survived to 53 weeks—comparable to adulthood in humans. The mice also were spared the enlarged liver commonly seen in GSD-Ia.
The results indicate that single base pair editing could provide long-term correction of the variant gene that causes GSD-Ia. Investigators are now recruiting people with the disorder for a clinical trial.

Reference

Arnaoutova I, Aratyn-Schaus Y, Zhang L, Packer MS, Chen HD, Lee C, Gautam S, Gregoire FM, Leboeuf D, Boule S, Fernandez TP, Huang V, Cheng LI, Lung G, Bannister B, Decker J, Leete T, Shuang LS, Bock C, Kothiyal P, Grayson P, Mok KW, Quinn JJ, Young L, Barrera L, Ciaramella G, Mansfield BC, Chou JY. Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia. Nature Communications DOI: 10.1038/s41467-024-54108-1 (2024)

Learn more about the Developmental Endocrinology, Metabolism & Genetics group: https://www.nichd.nih.gov/about/org/dir/affinity-groups/DEMG-EO.