title: Comparative therapeutic effects of velaglucerase alfa and imiglucerase in a Gaucher disease mouse model.
abstract: Gaucher disease type 1 is caused by the defective activity of the lysosomal enzyme, acid beta-glucosidase (GCase). Regular infusions of purified recombinant GCase are the standard of care for reversing hematologic, hepatic, splenic, and bony manifestations. Here, similar in vitro enzymatic properties, and in vivo pharmacokinetics and pharmacodynamics (PK/PD) and therapeutic efficacy of GCase were found with two human GCases, recombinant GCase (CHO cell, imiglucerase, Imig) and gene-activated GCase (human fibrosarcoma cells, velaglucerase alfa, Vela), in a Gaucher mouse, D409V/null. About 80+% of either enzyme localized to the liver interstitial cells and <5% was recovered in spleens and lungs after bolus i.v. injections. Glucosylceramide (GC) levels and storage cell numbers were reduced in a dose (5, 15 or 60 U/kg/wk) dependent manner in livers (60-95%) and in spleens ( approximately 10-30%). Compared to Vela, Imig (60 U/kg/wk) had lesser effects at reducing hepatic GC (p = 0.0199) by 4 wks; this difference disappeared by 8 wks when nearly WT levels were achieved by Imig. Anti-GCase IgG was detected in GCase treated mice at 60 U/kg/wk, and IgE mediated acute hypersensitivity and death occurred after several injections of 60 U/kg/wk (21% with Vela and 34% with Imig). The responses of GC levels and storage cell numbers in Vela- and Imig-treated Gaucher mice at various doses provide a backdrop for clinical applications and decisions.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: You-Hai
authors.initials: YH
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Sonya
authors.initials: S
authors.lastname: Barnes
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D020134:Catalytic Domain; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004795:Enzyme Stability / Q000187:drug effects; D005776:Gaucher Disease / Q000188:drug therapy*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism; D049231:Saposins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D049231:Saposins; D005962:Glucosylceramidase; C550184:Velaglucerase alfa, human; D010447:Peptide Hydrolases; C090568:imiglucerase