Ceramides are a group of naturally occurring molecules present in the cell membrane. However, excess ceramide is toxic to the cell. The enzyme acid ceramidase (AC) is responsible for breaking down excess ceramide to maintain an appropriate balance. Genetic mutations that disrupt normal AC function (AC deficiency) lead to rare metabolic conditions, such as Farber’s disease, which strikes infants, causing crippling arthritis, lung inflammation, nervous system degeneration, and liver disease and resulting in premature death. The only available therapeutic option for AC deficiency is bone marrow transplant, an invasive medical procedure with significant risks. The scientists at Plexcera Therapeutics have developed an approach to deliver functional AC protein. The purpose of this project is to support the pre-clinical development of this enzyme replacement therapy.
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 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 Farber’s 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 Farber’s 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.
Enzyvant, Durham, North Carolina
Alexander Solyom, M.D.
Plexcera Therapeutics, Vero Beach, Florida
Public Health Impact
There are no targeted treatments approved for disorders driven by a deficiency of AC enzyme activity. These metabolic conditions strike in childhood or adolescence, exert devastating effects on multiple organ systems, and lead to premature death by age 20.
TRND scientists completed a rigorous gap analysis and created a pre-clinical development plan that identified a set of critical experiments and milestones for the project. During the planning phase, the lead collaborators established a new business alliance, enabling them to use internal corporate resources to continue preclinical development.