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

项目总结/摘要 该提案要求为继续和延长利福平的IIa期临床试验提供资金，利福平是FDA- 批准的抗生素，用于治疗特发性婴儿高钙血症（IIH）， 编码CYP 24 A1基因的基因突变。IIH是一种不常见的代谢疾病，其特征在于 维生素D、骨化三醇的活化形式的血浆水平升高，并因此增加肠 钙吸收和骨吸收增加，共同引起高钙血症和高钙尿症。 虽然IIH通常出现在婴儿期，但患者表现出维生素D代谢的终身缺陷， 高钙尿症、肾结石和肾功能不全。CYP 24 A1编码24-羟化酶， 代表维生素D代谢物失活的主要途径，双等位基因突变引起大多数 IIH的常见和严重形式。这一途径的丧失使得骨化三醇的血浆水平过度升高， 克服了应该下调骨化三醇产生的反馈机制。只有一个人的病人 有缺陷CYP 24 A1等位基因具有不太严重的表型。目前没有具体的长期治疗方法， CYP 24 A1突变患者和常规护理包括尽量减少阳光照射，低钙， 饮食，避免富含维生素D的食物和维生素D补充剂。这种做法并不能降低风险 然而，肾钙化和肾功能不全可能导致骨密度降低。因此，有一个 对这种疾病安全有效治疗的显著未满足的医疗需求。我们有令人信服的数据 支持将抗生素利福平重新用于诱导CYP 3A 4表达的治疗方法， 一种在肝脏和肠道中表达的酶，为维生素C的失活提供替代途径 D代谢物。该项目的长期目标是为患者的医学治疗开发新的策略 伴有IIH和其他形式的高钙尿症和肾结石，这些疾病与血浆 骨化三醇本申请的目的是确定利福平的最佳安全有效剂量， 使血清和尿液钙水平正常化，并减少肠道对钙的吸收（主要结果）。 我们的两个互补目标是评估这些主要结局与血浆相关的程度 利福平水平、CYP 3A 4诱导、CYP 3A 4基因多态性和其他影响CYP 3A 4的基因 矿物质代谢和维生素D代谢产物的血浆水平的变化，并确定 CYP 24 A1突变对骨骼健康的影响我们的中心假设是利福平对CYP 3A 4的诱导作用会降低 骨化三醇水平，从而减少肠道对钙的吸收，我们预计， CYP 3A 4诱导的程度。我们有机会接触到必要的研究课题以及专门知识和资源 来进行这些研究。我们的方法是创新的，因为它提出了重新利用一个特点鲜明，安全 药物作为目前缺乏有效治疗的疾病的主要疗法的新作用。

Project Summary/Abstract This proposal requests funding for continuation and extension of a phase IIa clinical trial of rifampin, an FDA- approved antibiotic, for safety and efficacy as a treatment for idiopathic infantile hypercalcemia (IIH) due to mutations in the gene encoding CYP24A1 gene. 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 and increased bone resorption that together cause hypercalcemia and hypercalciuria. Although IIH typically presents in infancy, patients manifest a life-long defect in vitamin D metabolism that results in hypercalciuria, nephrolithiasis, and renal insufficiency. CYP24A1 encodes the 24-hydroxylase enzyme that represents the principal pathway for inactivation of vitamin D metabolites, and biallelic mutations cause the most common and severe form of IIH. Loss of this pathway allows plasma levels of calcitriol to rise excessively and overcomes feedback mechanisms that should downregulate production of calcitriol. Patients who carry only one defective CYP24A1 allele have a less severe phenotype. There is at present no specific long-term treatment for patients with CYP24A1 mutations and conventional care consists of minimizing sunlight exposure, a low calcium diet, and avoidance of vitamin D-rich foods and vitamin D supplements. This approach does not reduce the risk of renal calcification and renal insufficiency, however, and may lead to low bone density. Thus, there is a significant unmet medical need for safe and effective treatments for this disorder. We have compelling data supporting a therapeutic approach in which the antibiotic rifampin is repurposed to induce expression of CYP3A4, an enzyme that is expressed in the liver and intestine, to provide an alternative pathway for inactivation of vitamin D metabolites. The long-term goal of this project is 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 two 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 other genes that influence mineral metabolism, and changes in plasma levels of vitamin D metabolites and to determine the effect of CYP24A1 mutations on bone health. Our central hypothesis is that induction of CYP3A4 by rifampin will reduce levels of calcitriol and thereby decrease intestinal absorption of calcium and we expect that benefits will be related to the extent of CYP3A4 induction. 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.