Novel Oral Therapy For the Mucopolysaccharidoses

描述(由申请人提供)： 酶替代疗法(ERT)可用于其中三种MPS，但不能显著改善软骨、骨骼或脊柱疾病。因此，治疗MPS患者的这些异常是一个重要的未得到满足的医疗需求。聚硫酸戊聚糖(PPS)是FDA批准的一种口服药物，在几种疾病的动物模型上具有强大的抗炎和临床效果，包括骨关节炎和椎间盘退变。它目前被批准用于间质性膀胱炎患者，其 安全性已通过临床试验得到证明。在这项建议中，PPS将用于不同年龄的MPS VI大鼠，包括怀孕母亲，并将通过运动分析、骨密度和结构的显微CT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来评估PPS对软骨、骨骼和脊柱疾病的增龄效应。目标1将研究不同年龄的MPS VI动物口服PPS的情况；目标2将评估口服PPS治疗的剂量相关效应；AIM 3将比较口服PPS与皮下和肌肉内治疗；AIM 4将评估ERT/PPS联合治疗相对于ERT或PPS单独治疗的益处。PPS可能代表着MPS的第一个口服药物，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和直接的影响。

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.