Journal
BBA CLINICAL
Volume 7, Issue -, Pages 85-96Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbacli.2017.02.001
Keywords
Enzyme replacement; Ceramide; Arthritis; Mouse model
Categories
Funding
- National Institutes of Health [R01DK54801]
- Plexcera Therapeutics
Ask authors/readers for more resources
A series of studieswere carried out in Farber disease (OMIM #228000) cells and mice to evaluate the feasibility of enzyme replacement therapy (ERT) for this disorder. Media from Chinese hamster ovary (CHO) cells overexpressing human recombinant acid ceramidase (rhAC) was used to treat fibroblasts froma Farber disease patient, leading to significantly reduced ceramide. Wealso found that chondrocytes fromFarber disease mice had amarkedly abnormal chondrogenic phenotype, and this was corrected by rhAC as well. Acute dosing of rhAC in Farber mice confirmed the enzyme's bioactivity in vivo, and showed that it could be safely administered at doses up to 50 mg/kg. These studies also revealed little or no re-accumulation of ceramide in tissues for at least 7 days after enzyme administration. Once weekly administration of rhAC moderately improved survival of the mice, which could be enhanced by starting enzyme administration at an earlier age (3 days vs. 3 weeks). Repeat administration of the enzyme also led to normalization of spleen size, significantly reduced plasma levels of monocyte chemoattractant protein 1 (MCP-1), reduced infiltration of macrophages into liver and spleen, and significantly reduced ceramide and sphingosine in tissues. Overall, we conclude that ERT should be further developed for this debilitating and life-threatening disorder. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available