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 [31].
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 [101], or by oxLDL-mediated sphingomyelinase activation [103].
