Novel Oral Therapy For the Mucopolysaccharidoses

粘多糖症的新型口服疗法

• 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
• 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

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（Erts）可用于三种MPS，但不能显著改善软骨、骨或脊柱疾病。因此，MPS患者中这些异常的治疗代表了一个重要的未满足的医疗需求。多硫酸戊聚糖（PPS）是FDA批准的口服药物，在包括骨关节炎和椎间盘退变在内的多种疾病的动物模型中具有强效抗炎和临床作用。它目前被批准用于间质性膀胱炎患者， 安全性已通过临床试验得到证实。在本提案中，PPS将对不同年龄的MPS VI大鼠（包括妊娠母体）给药，并将通过动力试验、骨密度和结构的microCT分析、组织学、免疫组织化学、生物化学以及骨、软骨和脊柱组织的结构和组成的生物力学分析，评价对软骨、骨和脊柱疾病的年龄相关影响。目的1将检查PPS对不同年龄的MPS VI动物的经口给药;目的2将评价经口PPS治疗的剂量相关效应;目的3将比较经口PPS与皮下和肌内给药;目的4将评价ERT/PPS联合治疗相对于ERT或PPS单独治疗的获益。PPS可能代表MPS的第一种口服药物，如果这些实验成功，可能会对这些疾病患者的治疗和管理产生非常高的直接影响。