Pompe disease beyond the GAA gene: genetic modifiers, cellular pathways, gene therapy, and precision medicine

Abstract

Pompe disease is caused by biallelic pathogenic variants in GAA and deficiency of lysosomal acid alpha-glucosidase, yet GAA genotype alone does not fully explain the striking variability in age at onset, organ involvement, rate of progression, or therapeutic response. We suggest that Pompe disease should increasingly be considered a systemic disorder in which the main glycoside hydrolase glycogen-storage defect is associated with failure of autophagy, mitochondrial and calcium disturbances, oxidative stress, tissue vulnerability, disease-associated immunometabolic alterations, and, in treated patients, immune responses to therapeutic enzyme replacement. This perspective extends the mutation-centred framework highlighted by recent GAA variant studies and asks how modifier biology can be translated into clinically useful stratification. Patient-derived iPSC models and increasingly accurate animal models offer a chance to test genotype-specific mechanisms, and the efficacy of combination therapies, and multi-omic profiling could be used to discover modifiers and biomarkers that could differentiate patients with similar primary genotypes. However, the poor delivery of conventional enzyme replacement therapy to skeletal muscle and the central nervous system also points to therapeutic approaches that target both the restoration of GAA and the downstream pathology. We present a research plan that will incorporate deep phenotyping, longitudinal multi-omics, patient-specific modelling, and tissue-specific therapeutic development. This kind of strategy may usher in an era of precision medicine for Pompe disease from a genotype-based diagnosis. We propose a research framework integrating deep phenotyping, longitudinal multi-omics, patient-specific modelling, and tissue-specific therapeutic development, including emerging gene-based strategies.