title: Nonclinical safety assessment of recombinant human acid sphingomyelinase (rhASM) for the treatment of acid sphingomyelinase deficiency:the utility of animal models of disease in the toxicological evaluation of potential therapeutics.
abstract: Recombinant human acid sphingomyelinase (rhASM) is being developed as an enzyme replacement therapy for patients with acid sphingomyelinase deficiency (Niemann-Pick disease types A and B), which causes sphingomyelin to accumulate in lysosomes. In the acid sphingomyelinase knock-out (ASMKO) mouse, intravenously administered rhASM reduced tissue sphingomyelin levels in a dose-dependent manner. When rhASM was administered to normal rats, mice, and dogs, no toxicity was observed up to a dose of 30mg/kg. However, high doses of rhASM≥10mg/kg administered to ASMKO mice resulted in unexpected toxicity characterized by cardiovascular shock, hepatic inflammation, adrenal hemorrhage, elevations in ceramide and cytokines (especially IL-6, G-CSF, and keratinocyte chemoattractant [KC]), and death. The toxicity could be completely prevented by the administration of several low doses (3mg/kg) of rhASM prior to single or repeated high doses (≥20mg/kg). These results suggest that the observed toxicity involves the rapid breakdown of large amounts of sphingomyelin into ceramide and/or other toxic downstream metabolites, which are known signaling molecules with cardiovascular and pro-inflammatory effects. Our results suggest that the nonclinical safety assessment of novel therapeutics should include the use of specific animal models of disease whenever feasible.
authors.affiliation: Department of Pharmacology and Toxicology, Genzyme Corporation, Framingham, MA 01701, USA. Electronic address: james.murray@genzyme.com.
authors.forename: James M
authors.initials: JM
authors.lastname: Murray
authors.affiliation: Department of Pharmacology and Toxicology, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: Department of Pathology, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Vitsky
authors.affiliation: Department of Pathology, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hawes
authors.affiliation: Department of Biologics Structural and Functional Research, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Chuang
authors.affiliation: Department of Biologics Structural and Functional Research, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Pacheco
authors.affiliation: Charles River Laboratories, Preclinical Services, Reno, NV 89511, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Department of Biologics Research and Development, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: McPherson
authors.affiliation: Department of Pathology, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.affiliation: Early Process Development, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Karey
authors.affiliation: Department of Pharmacology and Toxicology, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Andrews
mesh_terms: D061605:Administration, Intravenous; D000311:Adrenal Glands; D000818:Animals; D002518:Ceramides / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D056947:Enzyme Replacement Therapy; D005260:Female; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052536:Niemann-Pick Disease, Type A / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity; D013108:Sphingomyelin Phosphodiesterase / Q000008:administration & dosage* / Q000172:deficiency* / Q000633:toxicity; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D002518:Ceramides; D016207:Cytokines; D011994:Recombinant Proteins; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase
keywords: Acid sphingomyelinase; Animal model; Ceramide; Enzyme replacement therapy; Niemann–Pick disease; Toxicity biomarkers