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针对酸性鞘磷脂酶（ASM）缺乏的尼曼-皮克病（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，该研究已经分离和鉴定了编码人类和小鼠ASM的cDNA和基因组序列，大规模生产和鉴定了人类，重组酶，构建和鉴定了人类疾病的小鼠模型（例如ASMKO小鼠），在小鼠模型中对几种实验疗法进行了临床前评估，并启动了B型NPD患者的酶替代疗法（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，在小鼠模型中研究了肺和脑疾病的发病机制，并记录了该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)开发针对asm缺陷型NPD的新疗法。我们将评估一种使用免疫靶向ASM纳米载体的ERT新方法。这种新的靶向系统可以改善重组ASM进入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)探究asm缺陷型NPD的发病机制。我们将研究ASM缺乏如何“保护”肺纤维化，并确定抗ASM疗法（如RNAi）是否可用于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NPD患者和携带者的临床表现。我们期待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。与公共卫生相关：缺乏asm的NPD是一种毁灭性的、通常是致命的遗传疾病，目前尚无治疗方法。这项研究将利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。这些研究还将探讨ASM在健康和疾病中的更广泛作用，特别是ASM活性与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.