Enzyme Enhancers for the Treatment of Fabry and Pompe Disease

Abstract

Lysosomal storage disorders (LSD) are a group of heterogeneous diseases caused by compromised enzyme function leading to multiple organ failure. Therapeutic approaches involve enzyme replacement (ERT), which is effective for a substantial fraction of patients. However, there are still concerns about a number of issues including tissue penetrance, generation of host antibodies against the therapeutic enzyme, and financial aspects, which render this therapy suboptimal for many cases. Treatment with pharmacological chaperones (PC) was recognized as a possible alternative to ERT, because a great number of mutations do not completely abolish enzyme function, but rather trigger degradation in the endoplasmic reticulum. The theory behind PC is that they can stabilize enzymes with remaining function, avoid degradation and thereby ameliorate disease symptoms. We tested several compounds in order to identify novel small molecules that prevent premature degradation of the mutant lysosomal enzymes α-galactosidase A (for Fabry disease (FD)) and acid α-glucosidase (GAA) (for Pompe disease (PD)). We discovered that the expectorant Ambroxol when used in conjunction with known PC resulted in a significant enhancement of mutant α-galactosidase A and GAA activities. Rosiglitazone was effective on α-galactosidase A either as a monotherapy or when administered in combination with the PC 1-deoxygalactonojirimycin. We therefore propose both drugs as potential enhancers of pharmacological chaperones in FD and PD to improve current treatment strategies.

Identification of an Allosteric Binding Site on Human Lysosomal Alpha-Galactosidase Opens the Way to New Pharmacological Chaperones for Fabry Disease

“…A230T shows a faint band corresponding to the precursor form of AGAL. This is not induced by the treatment with acknowledged PCs, DGJ, galactose [50] or ambroxol [21], at the dosages commonly used to measure their chaperoning effect on transfected mutants, 0.020 mM, 100 mM or 0.040 mM respectively. However, DTP 6 mM promotes the maturation of A230T.…”

“…Ambroxol, a mucolytic agent used in the treatment of respiratory diseases, proved to be useful in association with DGJ to rescue some AGAL mutants [21]. Its mechanism of action is not clear since ambroxol is not specific for AGAL, but it is effective also on lysosomal beta-glucocerebrosidase [22] and alpha-glucosidase mutants [21].…”

“…Its mechanism of action is not clear since ambroxol is not specific for AGAL, but it is effective also on lysosomal beta-glucocerebrosidase [22] and alpha-glucosidase mutants [21]. …”

More than Expectorant: New Scientific Data on Ambroxol in the Context of the Treatment of Bronchopulmonary Diseases

“…A new potential treatment area for ambroxol, as suggested by the rising number of publications in this field, is the treatment of lysosomal storage disorders such as Morbus Gaucher [35][36][37][38][39][40][41][42]. In an uncontrolled pilot study, the symptoms of Morbus Gaucher patients did not worsen under ambroxol treatment for 6 months [43].…”

Inherited cardiomyopathies—Novel therapies

“…. The PPAR-γ agonist rosiglitazone, was also tested in a similar modal, and showed promising results, especially in combination with migalastat (Lukas, et al, 2015).…”