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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD028607-19
Application #
7799836
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Oster-Granite, Mary Lou
Project Start
1992-02-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
19
Fiscal Year
2010
Total Cost
$349,455
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Savi?, Radoslav; He, Xingxuan; Fiel, Isabel et al. (2013) Recombinant human acid sphingomyelinase as an adjuvant to sorafenib treatment of experimental liver cancer. PLoS One 8:e65620
Savic, Radoslav; Schuchman, Edward H (2013) Use of acid sphingomyelinase for cancer therapy. Adv Cancer Res 117:91-115
Desnick, R J; Schuchman, E H (2012) Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annu Rev Genomics Hum Genet 13:307-35
He, Xingxuan; Schuchman, Edward H (2012) Potential role of acid sphingomyelinase in environmental health. Zhong Nan Da Xue Xue Bao Yi Xue Ban 37:109-25
Ledesma, Maria Dolores; Prinetti, Alessandro; Sonnino, Sandro et al. (2011) Brain pathology in Niemann Pick disease type A: insights from the acid sphingomyelinase knockout mice. J Neurochem 116:779-88
Dhami, Rajwinder; He, Xingxuan; Schuchman, Edward H (2010) Acid sphingomyelinase deficiency attenuates bleomycin-induced lung inflammation and fibrosis in mice. Cell Physiol Biochem 26:749-60
Desnick, Jonathan P; Kim, Jungmin; He, Xingxuan et al. (2010) Identification and characterization of eight novel SMPD1 mutations causing types A and B Niemann-Pick disease. Mol Med 16:316-21
He, Xingxuan; Huang, Yu; Li, Bin et al. (2010) Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging 31:398-408
Rodríguez-Pascau, Laura; Gort, Laura; Schuchman, Edward H et al. (2009) Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients. Hum Mutat 30:1117-22

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