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: 10703482
• 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/10703482
• 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，以低甲状旁腺激素(PTH)和钙离子为特征。 级别。患者会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方法是钙和活性维生素D。然而， 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，尽管或可能是由于常规治疗而发生的。尽管我们发现 骨钙化增加可能有益于骨骼，终末器官的钙化可能是完全的或部分的 对这些并发症负有责任。登记、回顾和索赔研究报告了血管 HPT患者的钙化；我们记录了脑钙化，观察数据记录了冠状动脉 钙化。其他与HPT相关的代谢紊乱也可能起到一定作用。不幸的是， 发病机制、流行病学、自然病史以及HPT、终末器官疾病、血管疾病之间的联系 钙化和其他排列紊乱尚不清楚。这是一个重大的科学鸿沟，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、 以及实施预防HPT相关终末器官损害的新战略；以及(3)进行 导致HPT治疗范例取得进展的研究。鉴于Pth，这些差距尤其相关 治疗，一种正在开发的HPT的非标签治疗方法。甲状旁腺激素治疗有促钙化副作用报道 FDA登记的骨质疏松症及其在HPT钙化和终末器官疾病中的可能作用的试验不是 安全。事实上，尽管研究报告称，通过常规治疗管理的HPT与 肾功能下降，我们发现PTH患者的肾功能并没有下降，而是 常规疗法。此外，我们的数据表明，骨基因表达的改变与骨代谢紊乱之间存在联系。 钙。我们发现循环中的microRNA与低骨转换高度相关，这是 骨外钙化。数据表明，这些相同的MIR可能与血管钙化有关 发展。该应用程序将提供一种严格的标准化方法来收集 HPT对终末器官损害和钙化倾向的影响。我们的中心假设是，一个自然历史队列 HPT使研究终末器官并发症成为可能。我们还假设，终末器官疾病与 钙化倾向和严重程度。其目标是：1)建立一个预期的纵向跟踪队列 研究HPT患者终末器官损害的流行病学及临床影响；确定器官- HPT的特定生理后果；3)。阐明HPT相关性终末器官损害的决定因素 来自生化测试和钙化成像。这是第一次，在这个罕见的未来自然历史数据 疾病将定义与HPT相关的终末器官损害的动态模型。因此，这些数据对于 为制定、研究和实施减轻HPT相关并发症的战略提供信息。