Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice.
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmacological chaperone AT1001 (migalastat HCl; 1-deoxygalactonojirimycin HCl) prior to intravenous administration of enzyme replacement therapy improved the pharmacological properties of the enzyme. In this study, the authors investigated the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation. AT1001 increased the physical stability and reduced aggregation of ATB100 at neutral pH in vitro, and increased the potency for ATB100-mediated globotriaosylceramide reduction in cultured Fabry fibroblasts. In Fabry mice, AT1001 coformulation increased the total exposure of active enzyme, and increased ATB100 levels in cardiomyocytes, cardiac vascular endothelial cells, renal distal tubular epithelial cells, and glomerular cells, cell types that do not show substantial uptake with enzyme replacement therapy alone. Notably, AT1001 coformulation also leads to greater tissue globotriaosylceramide reduction when compared with ATB100 alone, which was positively correlated with reductions in plasma globotriaosylsphingosine. Collectively, these data indicate that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation.
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Su
S
Xu
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Yi
Y
Lun
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Nastry
N
Brignol
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Rick
R
Hamler
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Adriane
A
Schilling
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Michelle
M
Frascella
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Sean
S
Sullivan
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Robert E
RE
Boyd
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Kate
K
Chang
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Rebecca
R
Soska
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Anadina
A
Garcia
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Jessie
J
Feng
JCR Pharmaceuticals, Kobe, Hyogo, Japan.
Hidehito
H
Yasukawa
GlaxoSmithKline R&D, Ware, Hertfordshire, UK.
Carole
C
Shardlow
GlaxoSmithKline R&D, Ware, Hertfordshire, UK.
Alison
A
Churchill
GlaxoSmithKline R&D, King of Prussia, Pennsylvania, USA.
Amol
A
Ketkar
GlaxoSmithKline R&D, Ware, Hertfordshire, UK.
Nicola
N
Robertson
JCR Pharmaceuticals, Kobe, Hyogo, Japan.
Masahito
M
Miyamoto
JCR Pharmaceuticals, Kobe, Hyogo, Japan.
Kazutoshi
K
Mihara
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Elfrida R
ER
Benjamin
TranscripTx, Inc., San Francisco, California, USA.
David J
DJ
Lockhart
JCR Pharmaceuticals, Kobe, Hyogo, Japan.
Tohru
T
Hirato
GlaxoSmithKline R&D, Ware, Hertfordshire, UK.
Susie
S
Fowles
Amicus Therapeutics Inc, Cranbury, New Jersey, USA.
Kenneth J
KJ
Valenzano
Amicus Therapeutics Inc, Cranbury, New Jersey, USA. Electronic address: rkhanna@amicusrx.com.
Richie
R
Khanna
D000818:Animals; D004195:Disease Models, Animal; D004338:Drug Combinations; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000188:drug therapy* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000008:administration & dosage*; D009154:Mutation; D009842:Oligopeptides / Q000008:administration & dosage*; D013379:Substrate Specificity; D000519:alpha-Galactosidase / Q000008:administration & dosage*
D004338:Drug Combinations; D018832:Molecular Chaperones; D009842:Oligopeptides; D000519:alpha-Galactosidase; C525167:larazotide acetate