Pompe disease: from new views on pathophysiology to innovative therapeutic strategies.

Pompe disease (PD) is a metabolic myopathy caused by the deficiency of the lysosomal hydrolase acid α-glucosidase (GAA) and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the attenuated intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is at present the only approved treatment for PD, in addition to supportive and physical therapies. However, ERT shows limited efficacy in some patients and does not completely correct the disease phenotype. Recently, an improved knowledge of PD pathophysiology has provided clues to explain the limitations of ERT. A mechanical effect of lysosomal inclusions on muscle contractility has been proposed as a key factor of disease resulting in a severe loss of contractility. In addition, it has been shown that secondary abnormalities of housekeeping cellular functions, such as autophagy, have an important role in the pathogenesis of cell damage in PD. Abnormalities of intra-cellular trafficking of vesicles and membrane-bound proteins, such as the cation-independent mannose-6-phosphate receptor, may be deleterious for the efficacy of ERT. At present, new therapeutic strategies, in addition to ERT, are under investigation. An emerging strategy for the treatment of PD is pharmacological chaperone therapy, based on the use of chaperone molecules that assist the folding of mutated enzymes and improve their stability and lysosomal trafficking. Pre-clinical studies demonstrated a synergistic effect of pharmacological chaperones and ERT. Other approaches, also in a pre-clinical stage, include substrate reduction and gene therapy.