title: 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.
authors.affiliation: Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Lukas
authors.affiliation: Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Pockrandt
authors.affiliation: Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Seemann
authors.affiliation: 1] Leibniz Institute for Catalysis, University of Rostock, Rostock, Germany [2] Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Sharif
authors.affiliation: Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Runge
authors.affiliation: Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Pohlers
authors.affiliation: 1] Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany [2] Leibniz Institute for Catalysis, University of Rostock, Rostock, Germany.
authors.forename: Chaonan
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Gläser
authors.affiliation: Leibniz Institute for Catalysis, University of Rostock, Rostock, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Beller
authors.affiliation: Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.affiliation: Albrecht Kossel Institute, Medical University Rostock, Rostock, Germany.
authors.forename: Anne-Katrin
authors.initials: AK
authors.lastname: Giese
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000551:Ambroxol / Q000494:pharmacology*; D001629:Bezafibrate / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology*; D000795:Fabry Disease / Q000188:drug therapy / Q000201:enzymology; D015870:Gene Expression; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy / Q000201:enzymology; D057809:HEK293 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D000077205:Pioglitazone; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D055550:Protein Stability; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014162:Transfection; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism; D000520:alpha-Glucosidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D007976:Leupeptins; D061988:Proteasome Inhibitors; D011994:Recombinant Proteins; D045162:Thiazolidinediones; C067713:lactacystin; D017485:1-Deoxynojirimycin; D000551:Ambroxol; C090092:migalastat; C509951:GAA protein, human; D000520:alpha-Glucosidases; C576330:GLA protein, human; D000519:alpha-Galactosidase; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine; D000077205:Pioglitazone; D001629:Bezafibrate