# Longitudinal characterization of Gaac.1826dupA mice reveals the cardiac, myopathic and biochemical phenotypes of Pompe disease

## TL;DR

This study shows that a mouse model with a human-relevant mutation for Pompe disease exhibits key disease features, making it useful for testing treatments.

## Contribution

The study provides a long-term characterization of a Pompe disease mouse model with a human-relevant mutation.

## Key findings

- KI mice showed early-onset hypertrophic cardiomyopathy and cardiac functional decline.
- Biochemically, KI mice had decreased GAA activity and glycogen accumulation in multiple tissues.
- Despite disease features, KI mice had survival rates similar to wild-type mice.

## Abstract

Pompe disease (PD) is a rare autosomal recessive disorder caused by acid α-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Pathogenic GAA variants result in enzyme dysfunction and glycogen storage in cardiac, skeletal and smooth muscle, as well as in the central nervous system, driving both systemic and neurological manifestations. We have previously characterized a transgenic knock-in (KI) mouse carrying the Gaa c.1826dupA variant to 12 weeks of age, showing that it recapitulates key biochemical and phenotypic features of PD. Here, we extend this analysis to present a long-term characterization of this Gaa c.1826dupA KI mouse model by using physiological, behavioral, biochemical and histopathological assessments. KI mice exhibited early-onset hypertrophic cardiomyopathy with significant cardiac functional decline, reduced body mass, impaired skeletal muscle strength, locomotion, coordination and balance. Biochemically, KI mice showed decreased GAA activity and increased lysosomal glycogen accumulation in the heart, diaphragm, gastrocnemius and brain. Despite these abnormalities, survival did not differ from wild-type mice – a divergence from severe human PD but consistent with other murine models. Collectively, these findings support this KI model as a translational platform for therapeutic evaluation in PD.

Summary: This comprehensive natural history of a Pompe disease mouse model comprising a human-relevant mutation shows that it recapitulates key disease features, thereby, supporting its use in preclinical therapeutic testing.