Treatment of Acid Ceramidase Deficiency

National Center For Advancing Translational Sciences

Investigators

Linked publications & trials

Abstract

Ceramides are present at high concentrations in the cellular lipid bilayer across a range of tissues and organs, including the liver, spleen, musculoskeletal system, and lungs. Loss of acid ceramidase (AC) enzyme activity leads to toxic accumulation of ceramide in lysosomes and other organelles. Although macrophages can take up cells damaged by ceramide accumulation, they are unable to process the toxic ceramide itself. This inability results in a cascade of cell damage and apoptosis across these multiple tissues and organ systems. Enzyme replacement therapy is a well-established approach to treating metabolic disorders. The investigators at Plexcera have shown in patient-derived cellular models and animal models of Farbers disease that a recombinant human acid ceramidase (rhAC) is able to break down the accumulated ceramide to normal levels in some tissues. This rhAC therapeutic approach represents a platform technology with the potential to treat not only Farbers disease but also other rare conditions driven by lack of AC activity for which there are no effective therapies, such as spinal muscular atrophy with progressive myoclonic epilepsy. The TRND project team have developed a project plan encompassing the pre-clinical studies necessary to enable submission of an Investigational New Drug application with the Food and Drug Administration. The plan includes developing a suitable formulation of rhAC to facilitate clinical dosing, conducting toxicology studies to demonstrate drug safety, developing and validating the biochemical assays necessary to evaluate the drug product and its in vivo activity, and conducting patient-finding activities to facilitate a natural history study and eventual clinical trials.