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Acid Sphingomyelinase and Niemann-Pick Disease

酸性鞘磷脂酶和尼曼匹克病

基本信息

批准号：
9247906
负责人：
EDWARD H. SCHUCHMAN
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-23 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247906
关键词：
Address Animals Applications Grants Ceramidase Cessation of life Chimeric Proteins Clinical Complementary DNA DNA Data Development Disease Dose Enzymes FUS-1 Protein Funding Future Gene Transfer Genes Goals Grant Heat shock proteins Hemorrhage Hepatotoxicity Human Intercellular adhesion molecule 1 Investigation Knock-out Knockout Mice Lead Lipids Liver Liver diseases Lung Lysosomal Storage Diseases Mus Mutation Niemann-Pick Diseases Organ Outcome Pathogenesis Pathogenicity Pathology Patients Production Publications Recombinants Research Residual state SPHK1 enzyme Source Sphingosine Spleen Stem cell transplant Testing Tissues Toxic effect Visceral Work acid sphingomyelinase base cell type clinically relevant effective therapy enzyme replacement therapy experimental study gene therapy improved in vivo mouse model novel novel marker novel strategies novel therapeutics phase 1 study phase 2 study pre-clinical preclinical evaluation preclinical toxicity programs screening sphingosine kinase sphingosine-1-phosphate lyase therapy development uptake vector

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：