In conjunction, RVT-801 is a recombinant form of human acid ceramidase
(rhAC) being developed as a potential enzyme replacement therapy for acid ceramidase
deficiency, manifesting as Farber disease.
Enzyvant, a subsidiary of Roivant Sciences, has selected Avid Bioservices as the commercial drug substance manufacturer for RVT801, its recombinant human acid ceramidase
enzyme replacement therapy being developed as a potential treatment for Farber disease.
In an in vitro study, overexpression of acid ceramidase
protected murine fibroblasts from TNF[alpha]induced cell apoptosis by shifting elevated ceramide towards cell survival sphingosine-1-phosphate .
El Bawab, "Bimodal effect of advanced glycation end products on mesangial cell proliferation is mediated by neutral ceramidase
regulation and endogenous sphingolipids," The Journal of Biological Chemistry, vol.
Necrosome activation also favors ceramide production through the induction of the ceramidase
enzyme, and it promotes cytosolic calcium increase.
Wang et al., "Receptor-mediated activation of ceramidase
activity initiates the pleiotropic actions of adiponectin," Nature Medicine, vol.
As mentioned above, all sphingolipids are metabolically interconnected; therefore, CerS generated by the a-SMase are subsequently degraded by the ceramidase
to sphingosine which can be phosphorylated to S1P that subsequently can activate different receptors.
Liu, IRF8 Regulates Acid Ceramidase
Expression to Mediate Apoptosis and Suppresses Myelogeneous Leukemia, J.
In addition, inhibition of acid ceramidase
with ceranib-2 has been reported to lead to apoptotic cell death in 5RP7 cells (Vejselova et al., 2014), LNCaP prostate cancer cells (Kus et al., 2015), melanoma (Proksch et al., 2011) and hepatomas (Osawa et al., 2005).
Li et al., "Acid ceramidase
upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer," Molecular Therapy, vol.
Acer2 (alkaline ceramidase
2) regulates the hydrolysis of ceramides.
Singlet oxygen may also contribute indirectly to ceramide accumulation via oxLDL-mediated decrease in adiponectin, since the latter has ceramidase
activity , or by oxLDL-mediated sphingomyelinase activation .