ACID SPHINGOMYELINASE & NIEMANN-PICK DISEASE

酸性鞘磷脂酶

基本信息

批准号：
7935121
负责人：
EDWARD H. SCHUCHMAN
金额：
$ 16.95万
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：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7935121
关键词：
Anti-Inflammatory Agents Anti-inflammatory Antibodies Biodistribution Bleomycin Blood - brain barrier anatomy Brain Brain Diseases Cells Ceramides Classical Niemann-Pick Disease Clinical Complementary DNA Data Development Disease Disease Progression Dose Enzymes Fibrosis Funding Genes Genomics Genotype Goals Health Hereditary Disease Heterogeneity Histologic Human Immunoglobulin Fragments Individual Inflammation Inflammatory Inheritance Patterns Injection of therapeutic agent Intercellular adhesion molecule 1 Interleukin-13 Investigational Therapies Knockout Mice Lead Lung MAP Kinase Kinase Kinase 1 Mediating Mediator of activation protein Mus Mutation Niemann-Pick Diseases Organ Pathogenesis Patients Pattern Phenotype Public Health Pulmonary Fibrosis RNA Interference Recombinants Research Research Personnel Restriction fragment length polymorphism Role Severities Signal Transduction Simvastatin System Testing Therapy Clinical Trials Tissues acid sphingomyelinase chemokine clinically relevant cohort effective therapy enzyme replacement therapy human disease imprint improved in vivo inhibitor/antagonist insight large scale production mouse model nanocarrier neodymium pyrocatechin disulfonate novel paternal imprint preclinical evaluation prevent programs uptake

项目摘要

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.

描述（由申请人提供）：我们研究的总体目标是开发针对酸性鞘磷脂酶（ASM）缺陷型尼曼-匹克病（A 型和 B 型 NPD）的新疗法，并更好地了解这种疾病的发病机制。迄今为止，这项研究已经实现了编码人类和鼠 ASM 的 cDNA 和基因组序列的分离和表征、人类重组酶的大规模生产和表征、小鼠模型（例如 ASMKO 小鼠）的构建和表征。人类疾病、小鼠模型中几种实验疗法的临床前评估，以及在 B 型 NPD 患者中启动酶替代疗法 (ERT) 临床试验。我们还对这种疾病进行了首次基因型/表型研究，研究了小鼠模型中肺和脑疾病的发病机制，并记录了这种酶在神经酰胺介导的细胞信号传导中的新作用。在下一个资助期内，我们将继续使用人类疾病的小鼠模型来实现两个具体目标：1）为 ASM 缺陷的 NPD 开发新疗法。我们将评估使用免疫靶向 ASM 纳米载体的新 ERT 方法。这种新颖的靶向系统改善了重组 ASM 向 NPD 细胞的吸收和溶酶体递送，并增强了向体内多个临床相关器官（包括肺和脑）的递送。我们还将评估抗炎治疗如何影响 ASMKO 小鼠的肺、脑和其他器官特异性疾病表现； 2) 研究 ASM 缺陷 NPD 的发病机制。我们将研究 ASM 缺陷如何“保护”肺纤维化，并确定抗 ASM 疗法（例如 RNAi）是否可用于预防正常小鼠的纤维化。我们还将研究 ASM 基因 (SMPD-1) 的父系印记如何影响患者和携带者个体中 NPD 的临床表现。我们预计这些研究将继续为这种疾病的发病机制提供新的见解，并导致新的和改进的疗法的开发。与公共卫生的相关性：ASM 缺陷型 NPD 是一种毁灭性且往往致命的遗传性疾病，目前尚无治疗方法。这项研究将使用人类疾病的小鼠模型来开发和评估人类疾病的新疗法，并为疾病机制提供新的见解。这些研究还将调查 ASM 在健康和疾病中更广泛的作用，特别是 ASM 活动与肺纤维化之间的关系。