Workpackage 3

Enzyme enhancement by pharmacological chaperones in Pompe disease

Generoso Andria from the Federico II University (Naples, Italy) is the WPL.

The goal of workpackage 3 is to explore the use of enzyme enhancement by pharmacological chaperones, for the treatment of Pompe disease (PD).

PD, due to a-glucosidase (GAA) deficiency, is a good example of lysosomal storage disease (LSD) to employ since the therapeutic approach currently available (enzyme replacement therapy, ERT) is not able to rescue all the symptoms of the disease, particularly skeletal muscle involvement. The lack of efficacy of ERT on skeletal muscle is not a trivial issue, as skeletal muscle involvement in PD has a dramatic impact on clinical course, patients’ quality of life and lifespan.

The use of pharmacological chaperones in PD, recently studied in vitro by Partner 1, showed GAA enhancement in fibroblasts from patients with specific mutations of the GAA gene. These studies provided evidence that imino sugars act as pharmacological chaperones on GAA and suggested a possible use of these compounds in human therapy. One of the imino sugars studied, N-butyldeoxynojirimycin (Miglustat), is already commercially available, as a substrate reducing agent for the treatment of Gaucher disease. However, for the translation into the clinical practice of these in vitro studies, some points need to be addressed and will be investigated in this research programme:

1. The rate of GAA mutations that might be enhanced by pharmacological chaperones.

2. The effects of chaperone treatment on cellular phenotypes.

3. The studies on the effects of pharmacological chaperones on GAA in vivo as a pre-clinical step, before use of pharmacological chaperones in humans.

4. The possible use of pharmacological chaperones and ERT as a combination therapy in vitro and in vivo.