Calcitonin for treating X-linked hypophosphatemia

降钙素治疗 X 连锁低磷血症

• 批准号: 8193343
• 负责人: KARL Leonard INSOGNA
• 金额: $ 22.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193343
• 关键词: Address; Adult; Adverse effects; Alkaline Phosphatase; Anterior; Arthritis; Auditory; Biochemical; Biological; Blood; Calcitonin; Calcitriol; Calcium; Child; Childhood; Clinical; Clinical Trials; Cyclophosphamide; Data; Defect; Deformity; Dihydroxycholecalciferols; Disease; Dose; Enthesopathies; FDA approved; Failure; Fasting; Functional disorder; Gait; Genetic; Genetic Transcription; Growth; Homeostasis; Hormones; Hour; Hypophosphatemia; Incidence; Individual; Inherited; Intestines; Kidney; Lead; Lesion; Life; Ligaments; Link; Measures; Mediator of activation protein; Metabolism; Mixed Function Oxygenases; Mutation; Neprilysin; Nose; Operative Surgical Procedures; Oral; Osteomalacia; Pathway interactions; Patients; Pharmaceutical Preparations; Production; Proximal Kidney Tubules; Reporting; Research; Rickets; Secondary Hyperparathyroidism; Serum; Spinal; Subcutaneous Injections; Syndrome; Testing; Therapeutic; Tooth Diseases; Toxic effect; Treatment Protocols; Tubular formation; United States; Urine; base; bone; calcification; calcium absorption; calcium metabolism; conventional therapy; dental abscess; design; epiphyseal closure; falls; improved; inorganic phosphate; irritation; loss of function mutation; malformation; mineralization; novel; novel therapeutic intervention; prevent; skeletal; sodium phosphate; symporter; wasting

DESCRIPTION (provided by applicant): The pathophysiology of X-linked hypophosphatemia (XLH) was clarified with the report in 1995 by the HYP Consortium that mutations in the neutral endopeptidase PHEX are the genetic basis for this disorder. By a pathway that remains unclear, loss-of-function mutations in PHEX lead to elevated circulating levels of FGF23. It is now well established that FGF23 is the proximate biological mediator of this syndrome. FGF23 suppresses renal tubular phosphate reabsorption by inhibiting transcription of sodium phosphate co-transporters in the proximal renal tubule. It also suppresses 1-1 hydroxylase activity leading to low or low-normal serum levels of 1,25(OH)2vitamin D, which impairs intestinal phosphate and calcium absorption. These combined biochemical abnormalities result in defective skeletal mineralization manifested as rickets in children and osteomalacia in adults. Conventional therapy for XLH with oral phosphate and calcitriol has several limitations including a low therapeutic/toxicity ratio, and a failure to correct growth retardation in children or the enthesopathy seen in adults. In addition, this treatment regimen causes a further rise in circulating levels of FGF23. Thus, there is a pressing need for better therapy directed at the basic pathophysiology of XLH. As detailed in the Research Strategy, we have identified calcitonin as a novel suppressor of FGF23 production in XLH. A single, subcutaneous injection of calcitonin results in a sustained fall in FGF23 levels in patients with this disease that persists for 16 hrs after drug administration; a change not observed in control subjects. The fall in serum FGF23 is associated with a rise in serum phosphate and circulating levels of 1,25(OH)2vitamin D. These exciting data suggest a novel therapy for XLH. This exploratory clinical trial seeks to establish the efficacy of calcitonin in improving the biochemical abnormalities in untreated adults with XLH. We will test the hypothesis that calcitonin, by lowering circulating levels of FGF23 and raising serum levels of 1,25(OH)2vitamin D, improves phosphate homeostasis in XLH by pursuing the following specific aims: 1. Determine whether 3 months of nasal calcitonin administered at a dose of 400 IU/day significantly lowers integrated 24-hr serum levels of FGF23 in patients with XLH. 2. Evaluate whether nasal calcitonin improves phosphate homeostasis by raising the TmP/GFR and integrated 24 hr serum phosphate concentrations. 3. Assess whether nasal calcitonin improves calcium metabolism in patients with XLH by increasing integrated 24 hr serum levels of 1,25(OH)2vitamin D and enhancing intestinal calcium absorption, as estimated by 24-hr urine calcium. 4. Confirm that nasal calcitonin is well tolerated by quantifying side effects and nasal irritation during the trial. If successful, this study will provide proof-of-principal for the novel use of an FDA-approved drug in treating XLH. This approach, unlike conventional treatment, addresses the underlying pathophysiology in this disorder and would represent the first therapeutic advance for XLH in 30 years. PUBLIC HEALTH RELEVANCE: X-linked hypophosphatemia (XLH) is the most common form of inherited rickets and osteomalacia in the United States. XLH is caused by overproduction of a hormone call FGF23, which makes the body waste phosphate. This study is designed to determine if nasal calcitonin, an already approved drug in the USA, can lower blood levels of FGF23 and reduce phosphate wasting in patients with XLH.

描述（由申请人提供）： HYP 联盟 1995 年的报告阐明了 X 连锁低磷血症 (XLH) 的病理生理学，即中性内肽酶 PHEX 的突变是该疾病的遗传基础。 PHEX 的功能丧失突变通过一条尚不清楚的途径导致 FGF23 的循环水平升高。现在已明确 FGF23 是该综合征的直接生物介质。 FGF23 通过抑制近端肾小管中磷酸钠协同转运蛋白的转录来抑制肾小管磷酸盐重吸收。它还抑制 1-1 羟化酶活性，导致 1,25(OH)2 维生素 D 血清水平降低或低于正常水平，从而损害肠道磷酸盐和钙的吸收。这些综合生化异常导致骨骼矿化缺陷，表现为儿童佝偻病和成人骨软化症。使用口服磷酸盐和骨化三醇治疗 XLH 的传统疗法有一些局限性，包括治疗/毒性比低，以及无法纠正儿童生长迟缓或成人中出现的附着点病。此外，这种治疗方案会导致 FGF23 循环水平进一步升高。因此，迫切需要针对 XLH 基本病理生理学的更好治疗方法。正如研究策略中详细介绍的，我们已确定降钙素是 XLH 中 FGF23 产生的新型抑制剂。单次皮下注射降钙素会导致患有这种疾病的患者 FGF23 水平持续下降，并在给药后持续 16 小时；在对照受试者中未观察到变化。血清 FGF23 的下降与血清磷酸盐和 1,25(OH)2 维生素 D 循环水平的升高有关。这些令人兴奋的数据表明了 XLH 的新疗法。这项探索性临床试验旨在确定降钙素在改善未经治疗的 XLH 成人生化异常方面的功效。我们将检验以下假设：降钙素通过降低 FGF23 的循环水平和提高 1,25(OH)2 维生素 D 的血清水平，通过追求以下具体目标来改善 XLH 中的磷酸盐稳态： 1. 确定以 400 IU/天的剂量鼻用降钙素 3 个月是否显着降低患有以下疾病的患者的 FGF23 24 小时综合血清水平： XLH。 2. 评估鼻降钙素是否通过提高 TmP/GFR 和综合 24 小时血清磷酸盐浓度来改善磷酸盐稳态。 3. 评估鼻降钙素是否通过增加 1,25(OH)2 维生素 D 的 24 小时血清综合水平和增强肠道钙吸收（通过 24 小时尿钙估计）来改善 XLH 患者的钙代谢。 4. 通过在试验期间量化副作用和鼻刺激，确认鼻降钙素具有良好的耐受性。如果成功，这项研究将为 FDA 批准的药物治疗 XLH 的新用途提供原理证明。与传统治疗不同，这种方法解决了这种疾病的潜在病理生理学问题，并将代表 XLH 30 年来的首次治疗进展。 公共卫生相关性：X 连锁低磷血症 (XLH) 是美国最常见的遗传性佝偻病和骨软化症。 XLH 是由 FGF23 激素分泌过多引起的，这种激素会使身体浪费磷酸盐。本研究旨在确定鼻用降钙素（一种已在美国获批的药物）是否可以降低 XLH 患者血液中 FGF23 的水平并减少磷酸盐浪费。