The overall goal of this research is to use our unique mouse models of Types A &B Niemann-Pick disease (NPD) to develop new therapies for this disorder and to uncover novel pathogenic mechanisms.
Two aims are proposed.
Aim 1 : Preclinical Evaluation of Two New Therapies. In the first set of studies we will evaluate a novel enzyme enhancement approach using the heat shock protein, Hsp70. These experiments are based on a recent publication showing that Hsp70 enhanced residual ASM activity and reduced lysosomal pathology in cells from Type A and B NPD patients, a finding that has been supported by new in vivo data obtained since the previous submission. The second set of studies will continue our work aimed at improved delivery of ASM to the lung using ICAM-1. A """"""""proof-of-principle"""""""" gene transfer experiment will be undertaken that will use AAV8 vectors to express ASM/ICAM-1 fusion proteins in the livers of NPD mice. Uptake and efficacy of the fusion enzymes in the lung and other clinically important organs will be studied. New in vivo data also has been obtained to demonstrate the feasibility of this approach.
Aim 2 : Investigation of Novel Pathogenic Mechanisms Leading to ERT-Related Liver Toxicity. Preclinical ERT studies in ASM knockout (ASMKO) mice have shown that administration of recombinant ASM at doses above 5 mg/Kg results in liver bleeding, the release of liver enzymes, and death. We have recently found that sphingosine, not sphingomyelin, is the major accumulating lipid in the livers of these mice, and hypothesize that sphingosine storage is responsible, at least in part, for the ERT-associated toxicity. We will determine the source of accumulating sphingosine by evaluating the expression of ceramidases, sphingosine kinases and sphingosine-1-phosphate lyase in the ASMKO mice, and breed these animals to mice lacking sphingosine kinase-1 to determine the effects on ERT- associated liver toxicity. These results should provide a mechanistic basis for the clinical observations in the mice, and also may lead to new strategies to overcome this toxicity.

Public Health Relevance

ASM deficiency (Types A and B Niemann-Pick disease;NPD) is a debilitating and often fatal lysosomal storage disease. Research in this grant application will use mouse models of NPD to evaluate two novel treatment approaches, and to gain a further understanding of the pathogenic mechanisms leading to liver disease and enzyme replacement therapy-related liver toxicity. Clinically important questions will be addressed, and the results should have high translational value for this and other lysosomal storage diseases.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Method to Extend Research in Time (MERIT) Award (R37)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Krotoski, Danuta
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Garnacho, Carmen; Dhami, Rajwinder; Solomon, Melani et al. (2017) Enhanced Delivery and Effects of Acid Sphingomyelinase by ICAM-1-Targeted Nanocarriers in Type B Niemann-Pick Disease Mice. Mol Ther 25:1686-1696
Schuchman, Edward H; Desnick, Robert J (2017) Types A and B Niemann-Pick disease. Mol Genet Metab 120:27-33
McGovern, Margaret M; Dionisi-Vici, Carlo; Giugliani, Roberto et al. (2017) Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Genet Med 19:967-974
Acuña, Mariana; Martínez, Pablo; Moraga, Carol et al. (2016) Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B. Eur J Hum Genet 24:208-13
Lee, Hyun; Lee, Jong Kil; Bae, Yong Chul et al. (2014) Inhibition of GM3 synthase attenuates neuropathology of Niemann-Pick disease Type C. by affecting sphingolipid metabolism. Mol Cells 37:161-71
Arroyo, Ana I; Camoletto, Paola G; Morando, Laura et al. (2014) Pharmacological reversion of sphingomyelin-induced dendritic spine anomalies in a Niemann Pick disease type A mouse model. EMBO Mol Med 6:398-413
Lee, Jong Kil; Jin, Hee Kyung; Park, Min Hee et al. (2014) Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease. J Exp Med 211:1551-70
Lee, Hyun; Lee, Jong Kil; Park, Min Hee et al. (2014) Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons. Nat Commun 5:5514
McGovern, Margaret M; Lippa, Natalie; Bagiella, Emilia et al. (2013) Morbidity and mortality in type B Niemann-Pick disease. Genet Med 15:618-23
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

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