Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease.
Fabry disease, an X-linked glycosphingolipid storage disorder, is caused by the deficient activity of α-galactosidase A (α-Gal A). This results in the lysosomal accumulation in various cell types of its glycolipid substrates, including globotriaosylceramide (GL-3) and lysoglobotriaosylceramide (globotriaosyl lysosphingolipid, lyso-GL-3), leading to kidney, heart, and cerebrovascular disease. To complement and potentially augment the current standard of care, biweekly infusions of recombinant α-Gal A, the merits of substrate reduction therapy (SRT) by selectively inhibiting glucosylceramide synthase (GCS) were examined. Here, we report the development of a novel, orally available GCS inhibitor (Genz-682452) with pharmacological and safety profiles that have potential for treating Fabry disease. Treating Fabry mice with Genz-682452 resulted in reduced tissue levels of GL-3 and lyso-GL-3 and a delayed loss of the thermal nociceptive response. Greatest improvements were realized when the therapeutic intervention was administered to younger mice before they developed overt pathology. Importantly, as the pharmacologic profiles of α-Gal A and Genz-682452 are different, treating animals with both drugs conferred the greatest efficacy. For example, because Genz-682452, but not α-Gal A, can traverse the blood-brain barrier, levels of accumulated glycosphingolipids were reduced in the brain of Genz-682452-treated but not α-Gal A-treated mice. These results suggest that combining substrate reduction and enzyme replacement may confer both complementary and additive therapeutic benefits in Fabry disease.
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
Karen M
KM
Ashe
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
Eva
E
Budman
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
Dinesh S
DS
Bangari
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
Craig S
CS
Siegel
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
Jennifer B
JB
Nietupski
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
Bing
B
Wang
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Robert J
RJ
Desnick
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
Ronald K
RK
Scheule
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
John P
JP
Leonard
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
Seng H
SH
Cheng
Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
John
J
Marshall
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006017:Glycolipids / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011812:Quinuclidines / Q000008:administration & dosage*; D013107:Sphingolipids / Q000378:metabolism*; D014281:Trihexosylceramides / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000008:administration & dosage / Q000378:metabolism
D002219:Carbamates; D006017:Glycolipids; D011812:Quinuclidines; D013107:Sphingolipids; D014281:Trihexosylceramides; C063288:globotriaosyl lysosphingolipid; C018549:globotriaosylceramide; C000608118:venglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D000519:alpha-Galactosidase