Lysosomal alpha-glucosidase (GAA) (GAA)

Lysosomal alpha-glucosidase (GAA) is an essential hydrolase located within the lysosome that catalyzes the breakdown of glycogen into glucose by cleaving alpha-1,4 and alpha-1,6 glycosidic bonds (UniProt P10253). A deficiency in GAA activity results in Pompe disease, also known as glycogen storage disease type II, which is characterized by the progressive accumulation of lysosomal glycogen in muscle tissues, leading to cardiomyopathy and respiratory failure (NIH GARD). Therapeutic interventions for this condition include enzyme replacement therapies (ERT) such as alglucosidase alfa and avalglucosidase alfa, which aim to restore enzymatic activity in affected cells (FDA). Additionally, pharmacological chaperones like miglustat are sometimes used in combination with ERT to stabilize the enzyme and improve its lysosomal uptake (PubMed PMID: 28104254). Monitoring the efficacy of these treatments typically involves measuring GAA activity levels and tracking biomarkers such as urinary glucose tetrasaccharide (Glc4) (PubMed PMID: 25533963). The development of next-generation ERTs focuses on improving the targeting of the enzyme to skeletal muscle via the cation-independent mannose-6-phosphate receptor (PubMed PMID: 33035447).

Other names

Acid alpha-glucosidaseAcid maltaseAlpha-1,4-glucosidaseGlucosidase alpha acidAgalsidase

Enzyme replacement therapy (ERT) provides exogenous recombinant human GAA to restore lysosomal glycogen degradation, while pharmacological chaperones stabilize the enzyme to improve trafficking and half-life (FDA; PubMed PMID: 28104254).