The use of muscle-specific, liver-detargeted adeno-associated virus (AAV) gene therapy appears to be effective in acid α-glucosidase (GAA) negative mice and could be a promising therapeutic alternative for patients with Pompe disease (PD), according to a recently published study in the Journal of Inherited Metabolic Disease.

Enzyme replacement therapy has greatly improved the overall survival and prognosis of patients with late onset PD and infantile onset PD, the researchers noted. However, despite sustained improvement in cardiac function, respiratory and muscle function eventually decreases in patients with infantile onset PD despite receiving appropriate treatment, they added.

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In vivo, gene therapy with AVV vectors has shown promising results in several studies. Approaches targeting the liver led to a significant decrease in muscle glycogen accumulation, but the high replication rate of liver cells resulted in transgene dilution and loss of efficacy in the long run. The muscle approach requires a high dose of vector that could lead to immune-led liver toxicity.

“Recently, a liver-muscle tandem promoter (LiMP) was proposed to control the immunogenicity of hGAA,” the authors wrote. “The use of LiMP to express a secretable form of hGAA with AAV9 resulted in the complete correction of glycogen accumulation in neonate Gaa−/− mice.”

The authors aimed to assess the effectiveness of a muscle-targeting capsid combined with LiMP to increase hGAA expression in the muscle of GAA-negative mice.

Results showed that 1 month after treatment administration, there was a significant increase of GAA activity in the heart and muscle in mice treated with AAV-LiMP in comparison to a control group. Similarly, the liver of mice receiving AAV-LiMP had a marked improvement in GAA activity 6 months after initial treatment. There was a complete recovery of muscle strength in the mice that received AAV/LiMP.

“In conclusion, the demonstration of the efficacy of a muscle-specific AAV capsid-promoter combination for the full rescue of PD manifestation in both neonate and adult Gaa−/− provides a potential therapeutic avenue for the infantile-onset form of this devastating disease,” the authors concluded.


Sellier P, Vidal P, Bertin B, et al. Muscle‐specific, liver‐detargeted adeno‐associated virus gene therapy rescues Pompe phenotype in adult and neonate gaa−/− mice. J Inherit Metab Dis. Published online May 19, 2023. doi:10.1002/jimd.12625