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: James M Murray, Anne Marie Thompson, Allison Vitsky, Michael Hawes, Wei-Lien Chuang, Joshua Pacheco, Stephen Wilson, John M McPherson, Beth L Thurberg, Kenneth P Karey, Laura Andrews
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 114 Issue 2 Pg. 217-25 (Feb 2015) ISSN: 1096-7206 [Electronic] United States
• PMID: 25092414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Ceramides
• Cytokines
• Recombinant Proteins
• Sphingomyelins
• Sphingomyelin Phosphodiesterase

Topics

• Administration, Intravenous
• Adrenal Glands
• Animals
• Ceramides (blood, metabolism)
• Cytokines (blood, immunology)
• Disease Models, Animal
• Dogs
• Drug Evaluation, Preclinical
• Enzyme Replacement Therapy
• Female
• Liver (metabolism, pathology)
• Lysosomes (metabolism)
• Macaca fascicularis
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Niemann-Pick Disease, Type A (drug therapy, metabolism)
• Rats
• Recombinant Proteins (administration & dosage, toxicity)
• Sphingomyelin Phosphodiesterase (administration & dosage, deficiency, toxicity)
• Sphingomyelins (metabolism)