ACID SPHINGOMYELINASE & NIEMANN-PICK DISEASE

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DESCRIPTION (provided by applicant): The overall goals of our research are to develop new therapies for acid sphingomyelinase (ASM)-deficient Niemann-Pick disease (Types A & B NPD), & to better understand the pathogenesis of this disorder. To date, this research has led to the isolation & characterization of cDNA & genomic sequences encoding human & murine ASM, the large-scale production & characterization of human, recombinant enzyme, construction & characterization of mouse models (e.g., ASMKO mice) for the human disorder, preclinical evaluation of several experimental therapies in the mouse models, & the initiation of enzyme replacement therapy (ERT) clinical trials in Type B NPD patients. We have also carried out the first genotype/phenotype studies on this disorder, investigated the pathogenesis of lung & brain disease in the mouse model, & documented a novel role for this enzyme in ceramide-mediated cell signaling. In the next funding period we will continue to use mouse models of the human disorder to undertake two specific aims: 1) Develop New Therapies for ASM-Deficient NPD. We will evaluate a new ERT approach using immunotargeted ASM nanocarriers. This novel targeting system results in improved uptake and lysosomal delivery of recombinant ASM into NPD cells, as well as enhanced delivery to several clinically relevant organs in vivo, including the lung & brain. We will also evaluate how anti-inflammatory treatments impact the lung, brain, & other organ- specific disease manifestations in ASMKO mice; 2) Investigate the Pathogenesis of ASM-Deficient NPD. We will investigate how ASM deficiency "protects" against lung fibrosis, & determine if anti-ASM therapies (e.g., RNAi) can be used to prevent fibrosis in normal mice. We will also study how paternal imprinting at the ASM gene (SMPD-1) influences the clinical presentation of NPD in patients & carrier individuals. We anticipate that these studies will continue to provide new insights into the pathogenesis of this disorder, and lead to the development of new & improved therapies. Relevance to Public Health: ASM-deficient NPD is a devastating & often fatal genetic disease for which no treatment is currently available. This research will use mouse models of the human disease to develop & evaluate new therapies for the human disorder, & to provide new insights into the disease mechanism. These studies will also investigate the broader role of ASM in health & disease, in particular the relationship between ASM activity & pulmonary fibrosis.