Advancing Product Development for Hypoparathyroidism: A Prospective Natural History Study of the Clinical Outcomes and Regulation of Disordered Mineral Metabolism

推进甲状旁腺功能减退症的产品开发：对矿物质代谢紊乱的临床结果和调节的前瞻性自然历史研究

• 批准号: 10573824
• 负责人: THOMAS L. NICKOLAS
• 金额: $ 39.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-08-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573824
• 关键词: Advancing; Product; Development; Hypoparathyroidism; Prospective

Hypoparathyroidism (HPT) is a rare disorder characterized by low parathyroid hormone (PTH) and calcium levels. Patients suffer consequences of hypocalcemia, including paresthesias, arrhythmias, and seizures. Conventional treatment to prevent these life-threatening events is calcium and active vitamin D. However, complications of HPT, including kidney and cardiovascular disease, cataracts, basal ganglia calcifications and neuropsychiatric disorders, occur despite, and possibly due to, conventional treatment. Although we found increased bone calcification may be beneficial to the skeleton, calcification of end-organs may be fully or partially responsible for these complications. Registry, retrospective, and claims studies have reported vascular calcifications in HPT patients; we noted brain calcifications, and observational data document coronary artery calcifications. Other HPT-associated metabolic derangements may also be contributory. Unfortunately, the pathogenesis, epidemiology, natural history, and links between HPT, end-organ diseases, vascular calcifications, and other derangements are unclear. This represents a significant scientific gap and impedes the: (1) diagnosis, monitoring, mitigation, and prevention of HPT associated complications; (2) development, study, and implementation of new strategies to prevent HPT-associated end-organ damage; and (3) ability to conduct studies leading to advances in the HPT treatment paradigm. These gaps are particularly relevant in light of PTH treatment, a developing off-label therapeutic for HPT. PTH treatment had pro-calcific side effects reported in FDA registry trials for osteoporosis and its possible role in calcification and end-organ diseases in HPT are not clear. Indeed, although studies reported that HPT managed with conventional treatment was associated with kidney function decline, we found that kidney function did not decline in patients managed with PTH instead of conventional therapy. Also, our data suggest a link between altered bone gene expression and dysregulation of calcium. We identified circulating microRNAs highly associated with low bone turnover, a major risk factor for extra-skeletal calcification. Data suggest these same miRs may be involved in vascular calcification development. This application will provide a rigorous standardized approach to longitudinal data collection in HPT on end-organ damage and calcification propensity. Our central hypothesis is that a natural history cohort of HPT enables the study of end-organ complications. We also hypothesize that end-organ disease is related to calcification propensity and severity. The Aims are to: 1) Build a prospective cohort of longitudinally followed HPT patients to study the epidemiology and clinical impact of end-organ damage; 2). Determine the organ- specific physiologic consequences of HPT; 3). Elucidate determinants of HPT-associated end-organ damage from biochemical testing and calcification imaging. For the first time, prospective natural history data in this rare disease will define a dynamic model of HPT-associated end-organ damage. Thus, the data will be critical to inform development, study, and implementation of strategies to mitigate HPT-associated co-morbidities.

甲状旁腺功能减退症（HPT）是一种罕见的疾病，其特点是甲状旁腺激素（PTH）和钙低 程度.患者遭受低钙血症的后果，包括感觉异常、心律失常和癫痫发作。 预防这些危及生命的事件的常规治疗是钙和活性维生素D。然而，在这方面， HPT的并发症，包括肾脏和心血管疾病、白内障、基底节钙化和 神经精神障碍，尽管发生，并可能是由于，常规治疗。虽然我们发现 增加的骨钙化可能对骨骼有益，终末器官的钙化可能完全或部分 造成了这些并发症。登记研究、回顾性研究和索赔研究报告了血管 HPT患者中有钙化;我们注意到脑钙化，观察数据记录冠状动脉 钙化其他HPT相关的代谢紊乱也可能是促成因素。可惜 发病机制，流行病学，自然史，以及HPT，终末器官疾病，血管 钙化和其他紊乱尚不清楚。这是一个重大的科学差距，阻碍了： (1)HPT相关并发症的诊断、监测、缓解和预防;（2）开发、研究， 和实施新的策略，以防止HPT相关的终末器官损伤;和（3）进行 导致HPT治疗模式进步的研究。这些差距与PTH特别相关 治疗，一种正在开发的HPT标签外治疗药物。PTH治疗有促钙化副作用， FDA关于骨质疏松症及其在HPT钙化和终末器官疾病中的可能作用的注册试验， 清楚事实上，尽管研究报告说，HPT与常规治疗有关， 肾功能下降，我们发现，在用PTH而不是 常规治疗。此外，我们的数据表明，骨基因表达的改变和骨细胞生长因子的失调之间存在联系。 钙我们鉴定了与低骨转换高度相关的循环microRNA，这是骨代谢的主要风险因素。 骨骼外钙化数据表明，这些相同的miR可能参与血管钙化 发展该应用程序将提供一个严格的标准化方法， HPT对终末器官损伤和钙化倾向的影响。我们的中心假设是，一个自然历史队列的 HPT能够研究终末器官并发症。我们还假设终末器官疾病与 钙化倾向和严重程度。目的是：1）建立一个前瞻性队列， 研究HPT患者终末器官损害的流行病学和临床影响; 2）。确定器官- HPT的特定生理后果; 3）。阐明HPT相关终末器官损伤的决定因素 生化检测和钙化成像这是第一次，在这个罕见的前瞻性自然历史数据 疾病将定义HPT相关终末器官损伤的动态模型。因此，这些数据对于 为减轻HPT相关合并症的策略的制定、研究和实施提供信息。