Enzyme replacement therapy for Farber disease: Proof-of-concept studies in cells and mice.

A series of studies were 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 from a Farber disease patient, leading to significantly reduced ceramide. We also found that chondrocytes from Farber disease mice had a markedly 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.