NIEMANN-PICK DISEASE

A型和B型尼曼-匹克病（NPD）是由酸性鞘磷脂酶（ASM）缺陷引起的溶酶体贮积症。A型NPD是一种严重的婴儿神经退行性疾病，通常会导致三岁以下的死亡。B型NPD的特征是缺乏神经系统受累，表型谱范围从严重的多系统疾病和早期死亡到较温和的成年状态。B型NPD的主要表现包括浸润性肺病、肝脾肿大、高脂血症、儿童生长迟缓和青春期延迟。在病程早期区分A型和B型NPD的困难限制了预后信息，使计划生育复杂化，并干扰了早期治疗努力的候选人的选择。因此，利用基因型和表型之间的经验相关性来预测疾病严重程度的能力将具有重要价值。A型和B型NPD的治疗主要是支持性的，尽管骨髓移植在B型NPD患者中的成功率非常有限。酶替代疗法（ERT）在相关溶酶体贮积症（I型戈谢病）中的治疗成功，以及ERT在尼曼-皮克小鼠中的有效性，为在非神经元病性B型NPD患者中使用重组ASM进行临床试验提供了依据。因此，拟议的研究将侧重于确定A型和B型NPD的临床、影像学和生化表现与特定ASM突变之间的相关性。此外，还将评价ERT治疗B型NPD的安全性和有效性。因此，拟议研究的具体目的是：1）确定A型和B型NPD的自然史，并确定基因型/表型相关性的致病ASM突变，2）评估ERT对B型NPD的作用。将在B型NPD患者中进行FDA批准的I/II期临床试验，以确定静脉内施用不同剂量的重组人ASM的安全性和有效性。将进行一系列临床、生化和药理学研究，以评价药物的疗效和药代动力学。总之，这些研究应该提供重要的诊断和治疗信息，以改善诊断为NPD的患者的结果。

Types A and B Niemann-Pick disease (NPD) are lysosomal storage disorders caused by deficient acid sphingomyelinase (ASM). Type A NPD is a severe neurodegenerative disease of infancy that typically causes death by three years of age. Type B NPD is characterized by the lack of neurological involvement and a phenotypic spectrum ranging from severe multisystem disease and early demise, to a milder condition of adulthood. The principal manifestations of Type B NPD include infiltrative pulmonary disease, hepatosplenomegaly, hyperlipidemia, and growth retardation and delayed puberty in children. The difficulty in differentiating between Types A and B NPD early in the disease course limits prognostic information, complicates family planning, and interferes with the selection of candidates for early therapeutic endeavors. Therefore, the ability to predict disease severity using information derived from empiric correlations between genotype and phenotype would be of significant value. Treatment for Types A and B NPD is primarily supportive, although bone marrow transplantation has been attempted with very limited success in Type B NPD patients. The therapeutic success of enzyme replacement therapy (ERT) in a related lysosomal storage disorder, Type I Gaucher disease, coupled with the demonstrated effectiveness of ERT in the Niemann-Pick mouse, provide the rationale for a clinical trial using recombinant ASM in patients with non-neuronopathic Type B NPD. The proposed studies will therefore focus on determining correlations between the clinical, radiographic and biochemical manifestations of Types A and B NPD and specific ASM mutations. In addition, the safety and effectiveness of ERT for Type B NPD will be evaluated. Thus the specific aims of the proposed research are: 1) to determine the natural history of Types A and B NPD and identify causative ASM mutations for genotype/phenotype correlations and 2) to evaluate the role of ERT for Type B NPD. An FDA-approved phase I/II clinical trial will be performed in Type B NPD patients to determine the safety and effectiveness of varying doses of intravenously administered recombinant human ASM. A series of clinical, biochemical, and pharmacological studies will be performed in order to evaluate the therapeutic effectiveness as well as the pharmacokinetics of the drug. In sum, these studies should provide important diagnostic and therapeutic information to improve the outcome of patients diagnosed with NPD.