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

项目摘要/摘要 这项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)的安全性和有效性，原因是 编码细胞色素P24A1基因的基因突变。IIH是一种不常见的代谢疾病，其特征是 活化形式的维生素D和骨化三醇的血浆水平升高，从而增加肠道 钙的吸收和骨吸收的增加共同导致高钙血症和高钙尿。 尽管IIH通常出现在婴儿期，但患者表现出终身的维生素D代谢缺陷 高钙尿、肾结石和肾功能不全。CYP24A1编码24-羟基酶， 代表了维生素D代谢物失活的主要途径，而双等位基因突变导致了 常见和严重的IIH形式。这一途径的缺失使血浆骨化三醇水平过度升高，并 克服了应该下调骨化三醇产生的反馈机制。只携带一个的病人 有缺陷的CYP24A1等位基因的表型不那么严重。目前还没有特效的长期治疗方法。 CYP24A1突变患者的常规护理包括最大限度地减少阳光曝晒，低钙 饮食，避免富含维生素D的食物和维生素D补充剂。这种方法并不能降低风险 然而，这可能导致肾脏钙化和肾功能不全，并可能导致低骨密度。因此，有一个 对这种疾病的安全和有效治疗的重大未得到满足的医疗需求。我们有令人信服的数据 支持改变抗生素利福平的用途以诱导细胞色素P3A4表达的治疗方法， 一种在肝脏和肠道中表达的酶，为维生素的失活提供另一种途径 D代谢物。这个项目的长期目标是为病人的医疗开发新的策略。 IIH和其他形式的高钙尿症和肾结石，与血浆胰岛素水平升高有关 骨化三醇。本应用的目的是确定利福平的最佳安全有效剂量 使血清和尿钙水平正常化，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果与血浆相关的程度 利福平水平、细胞色素P3A4的诱导、细胞色素P3A4基因的多态和其他影响 矿物质代谢，以及血浆维生素D代谢物水平的变化 CYP24A1突变对骨骼健康的影响。我们的中心假设是利福平对细胞色素P3A4的诱导会减少 骨化三醇水平，从而减少肠道对钙的吸收，我们预计这一好处将与 达到诱导细胞色素P3A4的程度。我们可以获得必要的研究课题以及专业知识和资源 来继续这些研究。我们的方法是创新的，因为它建议重新定位具有良好特性和安全的 对于一种目前缺乏有效治疗的疾病，药物治疗将扮演一个新的角色。

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.