Progress and challenges of gene therapy for Pompe disease.

Pompe disease (PD) is a monogenic disorder caused by mutations in the acid alpha-glucosidase gene (). GAA is a lysosomal enzyme essential for the degradation of glycogen. Deficiency of GAA results in a severe, systemic disorder that, in its most severe form, can be fatal. About a decade ago, the prognosis of PD has changed dramatically with the marketing authorization of an enzyme replacement therapy (ERT) based on recombinant GAA. Despite the breakthrough nature of ERT, long-term follow-up of both infantile and late-onset Pompe disease patients (IOPD and LOPD, respectively), revealed several limitations of the approach. In recent years several investigational therapies for PD have entered preclinical and clinical development, with a few next generation ERTs entering late-stage clinical development. Gene therapy holds the potential to change dramatically the way we treat PD, based on the ability to express the gene long-term, ideally driving enhanced therapeutic efficacy compared to ERT. Several gene therapy approaches to PD have been tested in preclinical animal models, with a handful of early phase clinical trials started or about to start. The complexity of PD and of the endpoints used to measure efficacy of investigational treatments remains a challenge, however the hope is for a future with more therapeutic options for both IOPD and LOPD patients.