Gene editing treatment alleviates symptoms of rare metabolic disease in mouse models
2024
Challenge
Glycogen storage disease type Ia (GSD-Ia), otherwise known as von Gierke disease, impairs the body’s ability to break down glycogen, a form of sugar stored in the liver and muscles. While dietary approaches can reduce symptoms, they require strict adherence and do not alter the underlying genetic problem that causes them, nor do they prevent long-term complications. Gene therapies, on the other hand, offer a more durable solution for treating the disease. However, approaches that attempt to treat the disease by editing genes using the CRISPR/Cas9 technique have been limited by their inability to successfully alter the correct gene in a large number of cells.
Advance
IRP researchers, in collaboration with biotechnology company Beam Therapeutics, evaluated a new treatment called BEAM-301, which uses nanoparticles to introduce chemicals and enzymes into liver cells that work together to correct the genetic mutation responsible for von Gierke disease. Unlike CRISPR/Cas9, which makes genetic changes by slicing up a DNA molecule, the ‘base editing’ approach that BEAM-301 uses directly changes a single letter in the DNA code. Untreated mice carrying the mutation that causes von Gierke disease had symptoms resembling those typically seen in the disease and died prematurely, but BEAM-301 corrected the genetic error in up to 60 percent of the animals’ liver cells. The activity of the corrected gene in the liver cells was durable and exceeded the minimum needed to alleviate symptoms: it normalized blood sugar control, reduced problems in how the mice’s bodies processed nutrients, and extended their lives.
Impact
The study’s findings highlight the therapeutic potential of base editing as an approach for treating von Gierke disease. The results were promising enough that they led to the initiation of a phase I/II clinical trial testing the safety and effects of BEAM-301 in adult patients with the condition.
Publications
Arnaoutova I, Aratyn-Schaus Y, Zhang L, Packer MS, Chen H-D, 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. Nat Commun 15(1):9729, 2024. doi: 10.1038/s41467-024-54108-1.
This page was last updated on Friday, April 18, 2025