Novel Oral Therapy For the Mucopolysaccharidoses

粘多糖症的新型口服疗法

基本信息

批准号：
8627166
负责人：
CALOGERA Maria SIMONARO
金额：
$ 21.19万
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：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627166
关键词：
ADAMTS Age Age-Months Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibody Therapy Behavior Biochemical Biochemistry Biological Assay Biomechanics Bladder Bone Density Bone Diseases Bone Marrow Transplantation Cartilage Cartilage Diseases Cell Proliferation Chondrocytes Clinical Defect Degenerative polyarthritis Dentition Disease Disease Progression Documentation Dose Enzymes Evaluation Exhibits Eye FDA approved Family GAG Gene Goals Grooming Histologic Histology Immunohistochemistry Inflammation Inflammatory Inherited Interstitial Cystitis Intramuscular Intravenous infusion procedures Liver Medical Mesenchymal Stem Cells Modeling Monitor Mothers Mucopolysaccharidoses Mucopolysaccharidosis I S Mucopolysaccharidosis VI Nose Oral Oral Administration Pathology Patients Pentosan Polysulfate Performance Pharmaceutical Preparations Rattus Safety Serum Site Spinal Spinal Diseases Staging Structure Tail Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Tumor Necrosis Factor-alpha Urine Veins Vertebral column Western Blotting advanced disease age related aggrecanase base bone cell motility clinical effect cranium cytokine enzyme deficiency enzyme replacement therapy human TNF protein improved intervertebral disk degeneration novel pregnant public health relevance research clinical testing research study skeletal disorder subcutaneous treatment duration

项目摘要

DESCRIPTION (provided by applicant): Enzyme replacement therapies (ERTs) are available for three of the MPS, but do not significantly improve the cartilage, bone or spinal disease. Thus, treatment of these abnormalities in MPS patients represents an important unmet medical need. Pentosan polysulfate (PPS) is an FDA-approved, oral medication that has potent anti-inflammatory and clinical effects in animal models of several diseases, including osteoarthritis and intervertebral disc degeneration. It is currently approved for use in patients with interstitial cystitis, and its safety has been demonstrated through clinical testing. In this proposal PPS will be administered to MPS VI rats of various ages, including pregnant mothers, and the age-related effects on cartilage, bone and spinal disease will be evaluated by motility assays, microCT analyses of bone density and structure, histology, immunohistochemistry, biochemistry, and by biomechanical analysis of the structure and composition of bone, cartilage and spinal tissues. Aim 1 will examine oral administration of PPS to MPS VI animals of various ages; aim 2 will evaluate dose-related effects of oral PPS treatment; aim 3 will compare oral PPS to subcutaneous and intramuscular treatment; and aim 4 will evaluate the benefits of combined ERT/PPS treatment over ERT or PPS alone. PPS could represent the first oral medication for MPS, and if these experiments are successful could have a very high and immediate impact on the treatment and management of patients with these disorders.

描述（由申请人提供）：酶替代疗法 (ERT) 可用于三种 MPS，但不能显着改善软骨、骨或脊柱疾病。因此，治疗 MPS 患者的这些异常是一个重要的未满足的医疗需求。多硫酸戊聚糖 (PPS) 是一种 FDA 批准的口服药物，在骨关节炎和椎间盘退变等多种疾病的动物模型中具有有效的抗炎和临床效果。目前已被批准用于间质性膀胱炎患者，其疗效安全性已通过临床测试得到证实。在本提案中，PPS 将被给予不同年龄的 MPS VI 大鼠，包括怀孕的母亲，并且将通过运动测定、骨密度和结构的 microCT 分析、组织学、免疫组织化学来评估与年龄相关的对软骨、骨和脊柱疾病的影响、生物化学，并通过生物力学分析骨、软骨和脊柱组织的结构和成分。目标 1 将检查对不同年龄的 MPS VI 动物口服 PPS；目标 2 将评估口服 PPS 治疗的剂量相关效应；目标 3 将比较口服 PPS 与皮下注射和肌肉注射治疗；目标 4 将评估 ERT/PPS 联合治疗相对于单独 ERT 或 PPS 治疗的益处。 PPS 可能代表第一种治疗 MPS 的口服药物，如果这些实验成功，可能会对患有这些疾病的患者的治疗和管理产生非常高和直接的影响。