The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease.
Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency in alpha-galactosidase A (alpha-Gal A) activity and subsequent accumulation of the substrate globotriaosylceramide (GL-3), which contributes to disease pathology. The pharmacological chaperone (PC) DGJ (1-deoxygalactonojirimycin) binds and stabilizes alpha-Gal A, increasing enzyme levels in cultured cells and in vivo. The ability of DGJ to reduce GL-3 in vivo was investigated using transgenic (Tg) mice that express a mutant form of human alpha-Gal A (R301Q) on a knockout background (Tg/KO), which leads to GL-3 accumulation in disease-relevant tissues. Four-week daily oral administration of DGJ to Tg/KO mice resulted in significant and dose-dependent increases in alpha-Gal A activity, with concomitant GL-3 reduction in skin, heart, kidney, brain, and plasma; 24-week administration resulted in even greater reductions. Compared to daily administration, less frequent DGJ administration, including repeated cycles of 4 days with DGJ followed by 3 days without or every other day with DGJ, resulted in even greater GL-3 reductions that were comparable to those obtained with Fabrazyme. Collectively, these data indicate that oral administration of DGJ increases mutant alpha-Gal A activity and reduces GL-3 in disease-relevant tissues in Tg/KO mice, and thus merits further evaluation as a treatment for Fabry disease.
Khanna
Richie
R
Department of Pharmacology, Amicus Therapeutics, Cranbury, New Jersey 08512, USA. rkhanna@amicustherapeutics.com
Soska
Rebecca
R
Lun
Yi
Y
Feng
Jessie
J
Frascella
Michelle
M
Young
Brandy
B
Brignol
Nastry
N
Pellegrino
Lee
L
Sitaraman
Sheela A
SA
Desnick
Robert J
RJ
Benjamin
Elfrida R
ER
Lockhart
David J
DJ
Valenzano
Kenneth J
KJ
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014281:Trihexosylceramides / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D014281:Trihexosylceramides; D017485:1-Deoxynojirimycin; C018549:globotriaosylceramide; C090092:migalastat; D000519:alpha-Galactosidase