comparative therapeutic effects of velaglucerase alfa and imiglucerase in a gaucher disease mouse model比较治疗效果velaglucerase阿尔法和imiglucerase戈谢病小鼠模型.pdf

Comparative Therapeutic Effects of Velaglucerase Alfa and Imiglucerase in a Gaucher Disease Mouse Model 1,2 1,2 1 1,2 You-Hai Xu , Ying Sun , Sonya Barnes , Gregory A. Grabowski * 1 Division of Human Genetics, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio, United States of America, 2 Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, United States of America Abstract Gaucher disease type 1 is caused by the defective activity of the lysosomal enzyme, acid b-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 (,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 c