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; 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）：1995年的报告阐明了X连锁低磷酸血症（XLH）的病理生理学，该报告是由中性内肽酶PHEX中的突变是这种疾病的遗传基础。通过尚不清楚的途径，PHEX的功能丧失突变导致FGF23的循环水平升高。现在已经很好地确定FGF23是该综合征的近端生物学介体。 FGF23通过抑制磷酸钠共转运蛋白在近端肾小管中的转录来抑制肾小管磷酸盐的吸收。它还抑制1-1羟化酶活性，导致低正常或低正常的血清水平为1,25（OH）2Vitamin D，从而损害肠道磷酸盐和钙吸收。这些合并的生化异常导致骨骼矿化有缺陷，在儿童和成年人的骨质乳酸中表现为rick虫。对XLH进行口服磷酸盐和骨化三醇的常规治疗具有多个局限性，包括低治疗/毒性比，以及未能纠正儿童或成人中观察到的Enthisopathy的生长迟缓。此外，这种治疗方案导致FGF23循环水平进一步上升。因此，迫切需要更好地针对XLH的基本病理生理学。正如研究策略所详述的那样，我们已经确定降钙素是XLH中FGF23产生的新型抑制剂。降钙素的单一皮下注射导致该疾病患者的FGF23水平持续下降，药物给药后持续16小时。在对照对象中未观察到的变化。血清FGF23的下降与血清磷酸盐的升高和1,25（OH）2VitaminD的循环水平升高有关。这些令人兴奋的数据表明对XLH进行了新的疗法。这项探索性临床试验旨在确定降钙素在改善XLH未经治疗的成年人的生化异常方面的功效。我们将通过降低FGF23的循环水平并提高血清水平1,25（OH）2Vitamin D来测试降低钙蛋白的假设，从而改善XLH中XLH中的磷酸稳态，以下特定目的：1。确定3个月的鼻钙蛋白水平是否在400 IU级别的纳米酸盐中进行400 IU的2400 IU级别的均量。 XLH。 2。评估鼻钙蛋白是否通过提高TMP/GFR并整合24小时血清磷酸盐浓度来改善磷酸稳态。 3。评估鼻降钙素是否通过增加24小时的1,25（OH）2Vitamin D并增强肠道钙的摄入量来改善XLH患者的钙代谢，如24小时的尿液钙估计。 4。确认鼻坚立素在试验过程中通过量化副作用和鼻部刺激来耐受。如果成功的话，这项研究将为您提供新的FDA批准药物治疗XLH的药物的原理证明。这种方法与常规治疗不同，解决了该疾病中潜在的病理生理学，这将代表30年内XLH的第一个治疗进展。 公共卫生相关性：X连锁的低磷酸盐血症（XLH）是美国遗传性rick和骨质乳核酸的最常见形式。 XLH是由激素呼叫FGF23过量产生引起的，这使得人体浪费磷酸盐。这项研究旨在确定在美国已经批准的药物鼻钙蛋白是否可以降低FGF23的血液水平并减少XLH患者的磷酸盐浪费。