Repurposing rifampin to reduce elevated levels of blood and urine calcium in patients with inactivating mutations of CYP24A1

项目总结/摘要 该提案要求为利福平（一种FDA批准的抗生素）的IIa期临床试验提供资金， 和作为特发性婴儿高钙血症（IIH）的治疗的有效性。IIH是一种不常见的代谢疾病 其特征在于活化形式的维生素D、骨化三醇的血浆水平升高， 增加肠道对钙的吸收，导致高钙血症和高钙尿症。虽然IIH通常 在婴儿期出现，患者表现出终生的维生素D代谢缺陷，导致血尿，肾性血尿， 钙化和肾功能不全CYP 24 A1的双等位基因失活突变，该基因编码24- 羟化酶是维生素D代谢物失活的主要途径， 最常见和最严重的IIH。这种降解途径的丧失使得血浆中的骨化三醇水平降低， 过度上升，克服了负反馈机制，应该下调生产 骨化三醇目前尚无针对CYP 24 A1突变和IIH患者的特异性长期治疗， 传统的护理包括尽量减少阳光照射，低钙饮食，避免富含维生素D的食物。 食物和维生素D补充剂，但这种方法并不能降低肾钙化和肾损害的风险。 不足因此，对于这种疾病的安全有效的治疗存在显著未满足的医疗需求。 我们有令人信服的数据支持一种新的治疗方法， CYP 3A 4的表达，CYP 3A 4是一种在肝脏和肠道中表达的酶，当过度表达时， 为维生素D代谢物的失活提供了替代途径。该项目的长期目标是 利用调节维生素D代谢的酶途径的知识，开发新的策略， IIH和其他形式的高钙尿症和肾结石相关患者的药物治疗 血浆骨化三醇水平升高本申请的目的是确定最佳的安全和 使血清和尿钙水平正常化并减少肠吸收的有效剂量的利福平 钙（主要结果）。我们的补充目标是评估这些主要因素在多大程度上 结果与利福平的血浆水平、CYP 3A 4的诱导、CYP 3A 4基因的多态性 以及维生素D代谢物的血浆水平的变化。我们的中心假设是， 利福平将降低血浆和/或肠中骨化三醇的水平，从而降低肠内 钙的吸收。我们预计总体获益将与CYP 3A 4的程度密切相关 诱导我们的第二个目标是使用我们的结果来驱动临床试验模拟器， 制定一项更大规模的利福平治疗IIH的IIb期关键性试验方案。我们有必要的 学习科目和专业知识和资源，以进行这些研究。我们的方法是创新的，因为它 建议将一种具有良好特征的安全药物重新定位为一种新的药物，作为一种疾病的主要治疗方法。 目前缺乏有效的治疗方法。

Project Summary/Abstract This proposal requests funding for a phase IIa clinical trial of rifampin, an FDA-approved antibiotic, for safety and efficacy as a treatment for idiopathic infantile hypercalcemia (IIH). IIH is an uncommon metabolic condition characterized by elevated plasma levels of the activated form of vitamin D, calcitriol, and consequently increased intestinal absorption of calcium that leads to hypercalcemia and hypercalciuria. Although IIH typically presents in infancy, patients manifest a life-long defect in vitamin D metabolism that results in hematuria, renal calcification, and renal insufficiency. Biallelic inactivating mutations of CYP24A1, the gene encoding the 24- hydroxylase enzyme that represents the principal pathway for inactivation of vitamin D metabolites, cause the most common and severe form of IIH. The loss of this degradative pathway allows plasma levels of calcitriol to rise excessively and overcomes negative feedback mechanisms that should downregulate production of calcitriol. There is at present no specific long-term treatment for patients with CYP24A1 mutations and IIH, and conventional care consists of minimizing sunlight exposure, a low calcium diet, and avoidance of vitamin D-rich foods and vitamin D supplements, but this approach does not reduce the risk of renal calcification and renal insufficiency. Thus, there is a significant unmet medical need for safe and effective treatments for this disorder. We have compelling data supporting a novel therapeutic approach that repurposes rifampin to induce expression of CYP3A4, an enzyme that is expressed in the liver and intestine and when over expressed provides an alternative pathway for inactivation of vitamin D metabolites. The long-term goal of this project is to use knowledge of enzymatic pathways that regulate vitamin D metabolism to develop novel strategies for medical treatment of patients with IIH and other forms of hypercalciuria and nephrolithiasis that are associated with elevated plasma levels of calcitriol. The objective in this application is to determine the optimal safe and effective dose of rifampin that normalizes serum and urine levels of calcium and reduces intestinal absorption of calcium (primary outcomes). Our complementary goals are to evaluate the extent to which these primary outcomes are related to plasma levels of rifampin, induction of CYP3A4, polymorphisms in the CYP3A4 gene, and changes in plasma levels of vitamin D metabolites. Our central hypothesis is that induction of CYP3A4 by rifampin will reduce levels of calcitriol, in the plasma and/or intestine, and thereby decrease intestinal absorption of calcium. We expect that overall benefits will be strongly associated with the extent of CYP3A4 induction. Our secondary aim is to use our results to drive a clinical trials simulator that will inform our development of a protocol for a larger, Phase IIb pivotal trial of rifampin for IIH. We have access to the necessary study subjects and the expertise and resources to pursue these studies. Our approach is innovative because it proposes to repurpose a well-characterized and safe medication to a new role as a primary therapy for a disorder that currently lacks an effective treatment.