Therapeutic Options for the Management of Pompe Disease: Current Challenges and Clinical Evidence in Therapeutics and Clinical Risk Management

Abstract

Pompe disease is a genetic disorder produced by mutations in the GAA gene leading to absence or reduced expression of acid alpha-glucosidase, an enzyme that metabolizes the breakdown of glycogen into glucose. There are two main phenotypes, the infantile consisting of early onset severe weakness and cardiomyopathy, and the adult which is characterized by slowly progressive skeletal and respiratory muscle weakness. Enzymatic replacement therapy (ERT) has been available for Pompe disease for more than 15 years. Although the treatment has improved many aspects of the disease, such as prolonged survival through improved cardiomyopathy and acquisition of motor milestones in infants and slower progression rate in adults, ERT is far from being a cure as both infantile and adult patients continue to progress. This fact has prompted the development of improved or new enzymes and other treatments such as gene therapy or substrate reduction strategies. Here, we review the data obtained from randomized clinical trials but also from open-label studies published so far that have assessed the advantages and limitations of this therapy. Moreover, we also review the new therapeutic strategies that are under development and provide our opinion on which are the unmet needs for patients with this disease.

Keywords: Pompe disease; clinical trials; enzyme replacement therapy; genetic therapy; glycogen storage disease type II; recombinant human acid alpha-glucosidase.

Figure 1

Timeline showing the different clinical trials published since 2001.

Figure 2

Treatment strategies for Pompe disease. This figure shows the different available/under research treatment strategies for Pompe disease. RhGAA’s uptake is mediated by CI-MPR and, once inside the muscle fiber, is delivered into the cytoplasm and lysosomes where it breaks down glycogen. There are two different gene therapy strategies: one directed towards the liver and one towards the muscle fiber. In the first one GAA is synthesized by the liver, released into the bloodstream and later delivered to the muscle fiber. In the second one GAA is synthesized by the muscle fibre and acts locally. Autophagy suppression would inhibit the formation of autophagic vacuoles and consequently cell death. Inhibition of GYS1 would be a substrate reduction strategy. Created with BioRender.com.