ACID SPHINGOMYELINASE & NIEMANN-PICK DISEASE

描述(由申请人提供)：我们研究的总体目标是开发治疗酸性鞘磷脂酶(ASM)缺陷Niemann-Pick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。到目前为止，这项研究已经导致了编码人和小鼠ASM的cDNA和基因组序列的分离和表征，人和重组酶的大规模生产和表征，人类疾病小鼠模型(如ASMKO小鼠)的构建和表征，几种实验性小鼠模型的临床前评估，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第一次基因分型/表型研究，在小鼠模型中研究了肺和脑疾病的发病机制，并证明了这种酶在神经酰胺介导的细胞信号转导中的新作用。在下一个资助期，我们将继续使用人类疾病的小鼠模型来承担两个具体目标：1)为ASM缺乏的NPD开发新的治疗方法。我们将使用免疫靶向ASM纳米载体来评估一种新的ERT方法。这种新的靶向系统可以改善重组ASM对NPD细胞的摄取和溶酶体递送，并增强对体内几个临床相关器官的递送，包括肺和脑。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缺乏如何“保护”肺纤维化，并确定是否可以使用抗ASM疗法(例如，RNAi)来预防正常小鼠的纤维化。我们还将研究父亲在ASM基因(SMPD-1)上的印记如何影响患者和携带者的NPD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治疗方法的发展。与公共卫生的相关性：缺乏ASM的NPD是一种毁灭性的、往往是致命的遗传病，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针对人类疾病的新疗法，并为疾病机制提供新的见解。这些研究还将调查ASM在健康和疾病中的更广泛作用，特别是ASM活动和肺纤维化之间的关系。

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.