Invention:
The inventors have developed an aSMaseKO mouse model that can be utilized as a proof-of-concept for using the mutant enzyme in enzyme replacement studies in patients with Niemann-Pick disease (NPD). NPD is a rare, inherited disease that affects the body's ability to metabolize fat (cholesterol and lipids) within cells. The inventors suggest that the use of a mutant form of aSMase presents a novel approach for potential recombinant studies geared at restoring L-SMase activity and potentially avoiding the amplified inflammatory response attributed to S-SMase activity. Their current data demonstrate that mice expressing the mutant form of aSMase retain tissue sphingomyelin levels, but do not have S-SMase activity. Moreover, these mice do not exhibit loss of motor function or and retain Purkinje cells in the cerebellum, suggesting the mutation may serve to pave the way for enzyme replacement therapy (ERT) for NPD.
Background:
Acid sphingomyelinase is a lipid enzyme that hydrolyzes sphingomyelin to generate ceramide. This enzyme can be trafficked to the lysosome (L-SMase) or secreted from cells (S-SMase). Deficiency of acid sphingomyelinase (aSMase) results in Niemann-Pick disease (NPD) types A and B. NPD-A patients develop severe neurological and visceral pathology and typically do not survive past the age of 3, NPD-B patients generally live into adolescence or early adulthood and commonly do not manifest neurological symptoms. NPD patients lack both forms of aSMase (lysosomal, L-SMase and secretory, S-SMase), as do aSMase knockout (aSMaseKO) mice which have been used as a model for NPD. Homozygous aSMaseKO mice develop progressive lipid storage disease, mimicking disease in NPD-A.
Applications:
Advantages:
- Therapeutic treatment for a rare disease with no known cure
- Proof-of-concept mouse model
