Researchers managed to restore the function of the acid alpha-glucosidase (GAA) enzyme in fibroblasts derived from a patient with infantile-onset Pompe disease (IOPD) using genome editing techniques. They reported their findings at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting.

“The results presented herein underscore the potential of base and prime editing techniques as personalized therapeutics for not only patients with IOPD, but also patients with other genetic diseases,” the researchers said. 

The team first used an adenine base editor and a single guide RNA to target the GAA c.2227C>T (p.Q743*) nonsense mutation and a prime editor and prime editing guide RNA to target the GAA c.258dupC (p.N87Qfs*9) frameshift mutation in an in vitro, nonnuclear setting. They found that GAA c.2227C>T was base edited with 47% efficiency and GAA c.258dupC was edited with up to 29% efficiency, thereby establishing initial on-targeting efficiency.

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“Given that patients with >8% enzyme activity have an attenuated disease course, these editing efficiencies could translate to mitigation of disease progression for IOPD patients,” the researchers wrote.

Read more about the types of Pompe disease

They then tested the base-editing strategy in patient-derived fibroblasts. They reported that more than 80% of thymine at position c.2227 was restored to wild-type cytosine after just 4 days. GAA function was also detected at that point and peaked at day 35 above normal levels.

The researchers now plan to determine the precise editing efficiency of both approaches and further characterize the edited cells by assessing the levels of glycogen and proteins involved in autophagy and cellular stress. They will also assess editing efficiency in induced pluripotent stem cell-derived cardiomyocytes and skeletal myoblasts.

Pompe disease is caused by a mutation in the GAA gene, which encodes the GAA enzyme. This enzyme is essential for the breakdown of glycogen, so its deficiency leads to the accumulation of glycogen inside lysosomes, causing cardiac and skeletal myopathies.


Christensen C, Rha A, Kan SH, Harb J, Wang R. Genome editing restores acid alpha-glucosidase function in fibroblasts derived from a patient with infantile-onset Pompe disease. Poster presented at: American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting; May 16-19, 2022; Washington DC.