Pompe disease: from pathophysiology to therapy and back again

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Pompe disease is a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency.
• This deficiency leads to glycogen accumulation in lysosomes, primarily affecting cardiac and skeletal muscles.
• Current enzyme replacement therapy (ERT) is effective for cardiac issues but not skeletal muscle, highlighting an incomplete understanding of disease pathophysiology.

Purpose of the Study:

• To elucidate the complex pathophysiology of muscle damage in Pompe disease beyond lysosomal enlargement.
• To investigate the role of dysfunctional autophagy and lipofuscin accumulation in Pompe skeletal muscle.
• To understand how these cellular abnormalities impact the efficacy of enzyme replacement therapy.

Main Methods:

• Analysis of cellular abnormalities in Pompe skeletal muscle, focusing on lysosomal function and autophagy.
• Investigation of autophagosomal-lysosomal fusion defects and lipofuscin deposition.
• Evaluation of the impact of dysfunctional autophagy on enzyme replacement therapy delivery.

Main Results:

• Pompe skeletal muscle exhibits impaired autophagosomal-lysosomal fusion, a key defect in the autophagic pathway.
• Accelerated accumulation of lipofuscin, indicative of oxidative damage and mitochondrial dysfunction, is observed.
• These autophagic and lipofuscin abnormalities contribute significantly to muscle architecture damage and interfere with ERT delivery to lysosomes.

Conclusions:

• Muscle damage in Pompe disease is driven by more than just lysosomal enlargement, with dysfunctional autophagy and lipofuscin buildup playing critical roles.
• Impaired autophagy affects the trafficking and efficacy of enzyme replacement therapy.
• New therapeutic strategies targeting autophagy and substrate reduction show promise in preclinical models.