University of Arizona researchers have developed an acid sphingomyelinas knockout (aSMaseKO) mouse model as a proof-of-concept for using the mutant enzyme in enzyme replacement studies for Niemann-Pick disease (NPD). NPD is a rare, inherited disease that affects the body's ability to metabolize fat within cells. The inventors suggest that a mutant form of acid sphingomyelinas (aSMase) presents a novel approach for recombinant studies geared at restoring lysosomal aSMase (L-Smase) activity while avoiding the inflammatory response attributed to secretory aSMase (S-Smase) activity. Data demonstrates that mice expressing the mutant form of aSMase retain tissue sphingomyelin levels, but lack S-SMase activity. Moreover, these mice do not exhibit loss of motor function 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). aSMase deficiency causes NPD types A and B. NPD-A causes severe neurological and visceral pathology with patients rarely surviving past age 3. NPD-B patients generally live into adolescence or early adulthood and typically don't experience neurological symptoms. Both NPD patients and aSMaseKO mice lack both forms of aSMase (L-SMase and S-SMase), making mice a model for NPD. Homozygous aSMaseKO mice develop progressive lipid storage disease, mimicking NPD-A. Application:
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