NIEMANN-PICK DISEASE

尼曼匹克病

• 批准号: 6881373
• 负责人: MELISSA P WASSERSTEIN
• 金额: $ 12.96万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881373
• 关键词: Niemann Pick disease; beta N acetylhexosaminidase; biochemistry; biomarker; blood chemistry; clinical trial phase I; enzyme activity; enzyme therapy; gene mutation; genetic disorder; genetic markers; genotype; glycolysis; human subject; human therapy evaluation; pathologic process; patient oriented research; pharmacokinetics; phenotype; phosphodiesterases; radiography; recombinant proteins

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.

A型和B型尼曼 - 棘疾病（NPD）是由酸性鞘磷脂酶（ASM）引起的溶酶体储存障碍。 A型NPD是婴儿期的一种严重的神经退行性疾病，通常在三岁时导致死亡。 B型NPD的特征是缺乏神经学参与和表型谱系，从严重的多系统疾病和早期灭亡到成年的温和状况。 B NPD型的主要表现包括浸润性肺部疾病，肝肿瘤，高脂血症和生长迟缓以及儿童的青春期延迟。在疾病课程的早期，区分A类型和B NPD的困难限制了预后信息，使计划生育变得复杂，并干扰了为早期治疗努力选择候选人。因此，使用从基因型和表型之间的经验相关性得出的信息来预测疾病严重程度的能力将具有重要的价值。 A型和B型NPD的治疗主要支持，尽管在B型NPD患者方面已尝试以非常有限的成功进行了骨髓移植。酶替代疗法（ERT）在相关的溶酶体储存障碍，I型Gaucher疾病中的治疗成功，再加上ERT在Niemann-Pick小鼠中的有效性，为非抑制ASM患者的临床试验提供了基于临床试验的基本原理。因此，拟议的研究将着重于确定A和B NPD型的临床，放射线和生化表现以及特定ASM突变之间的相关性。另外，将评估ERT对B型NPD的安全性和有效性。因此，提出的研究的具体目的是：1）确定A类和B类型的自然历史，并确定基因型/表型相关性的病因ASM突变，以及2）评估ERT对于B型NPD的作用。将在B型NPD患者中进行一项由FDA批准的I/II期临床试验，以确定不同剂量的静脉注射重组人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，以评估药物的治疗有效性以及药代动力学。总而言之，这些研究应提供重要的诊断和治疗信息，以改善被诊断为NPD的患者的结果。