Calcitonin for Treating X-linked Hypophosphatemia

降钙素治疗 X 连锁低磷血症

• 批准号: 8319251
• 负责人: KARL Leonard INSOGNA
• 金额: $ 18.68万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319251
• 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.

描述(由申请人提供)：1995年HYP联合会的报告阐明了X连锁低磷血症(XLH)的病理生理学，报告称中性内肽酶PHEX的突变是这种疾病的遗传基础。通过一条尚不清楚的途径，PHEX功能丧失突变导致循环中FGF23水平升高。现已证实，FGF23是该综合征的直接生物介体。FGF23通过抑制近端肾小管磷酸钠共转运蛋白的转录，抑制肾小管磷酸盐的重吸收。它还抑制1-1羟基酶活性，导致血清1，25(OH)2维生素D水平偏低或低于正常水平，从而损害肠道磷酸盐和钙的吸收。这些组合的生化异常导致骨骼矿化缺陷，在儿童中表现为软骨病，在成人中表现为骨软化。口服磷酸盐和骨化三醇的传统疗法有几个局限性，包括治疗/毒性比低，以及未能纠正儿童的生长迟缓或成人的终末期疾病。此外，这种治疗方案还导致循环中FGF23水平的进一步升高。因此，迫切需要针对XLH的基本病理生理学进行更好的治疗。正如在《研究策略》中详细描述的那样，我们已经确定降钙素是一种新的抑制XLHFGF23产生的因子。单次皮下注射降钙素可导致这种疾病患者的FGF23水平持续下降，并在给药后持续16小时；在对照受试者中没有观察到这种变化。血清FGF23的下降与血磷和循环中1，25(OH)2维生素D水平的上升有关。这些令人兴奋的数据表明了一种治疗XLH的新方法。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疗效。我们将测试这一假设，即降钙素通过降低循环中FGF23的水平和提高血清1，25(OH)2维生素D的水平，通过追求以下特定目标来改善XLH的磷酸盐稳态：1.确定3个月的鼻用降钙素400IU/天是否显著降低XLH患者24小时血清FGF23的综合水平。2.评价鼻腔降钙素是否通过提高TMP/GFR和24小时血磷浓度来改善磷酸盐稳态。3.评估鼻腔降钙素是否通过增加24小时血清1，25(OH)2维生素D的积分水平以及通过24小时尿钙估计的肠道钙吸收来改善XLH患者的钙代谢。4.通过量化试验期间的副作用和鼻部刺激性，确认鼻腔降钙素耐受性良好。如果成功，这项研究将为FDA批准的药物治疗XLH的新用途提供原则证明。与常规治疗不同，这种方法解决了这种疾病的潜在病理生理学问题，并将代表着30年来XLH的第一个治疗进展。