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

重新利用利福平可降低 CYP24A1 失活突变患者的血钙和尿钙水平升高

基本信息

批准号：
10581278
负责人：
MICHAEL ALAN LEVINE
金额：
$ 63.18万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-23 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581278
关键词：
Affect Alleles Antibiotics Biological Blood Bone Density Bone Mineral Contents Bone Resorption C-telopeptide COVID-19 CYP3A4 gene CYP3A5 gene Calcitriol Calcium Caring Chronic Clinical Trials Collagen Type I Data Defect Diet Disease Dose Dual-Energy X-Ray Absorptiometry Enrollment Enzymes FDA approved Feedback Food Funding Genes Genetic Genetic Polymorphism Goals Grant Health Heterozygote Hypercalcemia Hypersensitivity Induced Mutation Infant Infantile hypercalcemia Intestinal Absorption Intestines Kidney Kidney Calculi Kidney Failure Life Liver Measures Medical Metabolic Metabolism Minerals Mission Mixed Function Oxygenases Monitor Morbidity - disease rate Mutation Nephrolithiasis Oral Osteogenesis Outcomes Research Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Plasma Production Rare Diseases Recurrence Request for Proposals Research Research Project Grants Resources Rifampin Role Safety Science Serum Serum Markers Study Subject Sun Exposure Testing Therapeutic Trabecular Bone Score United States National Institutes of Health Urine Variant Vitamin D Vitamin D supplementation Vitamins Work bone health bone turnover calcification calcium absorption calcium excretion design effective therapy efficacy evaluation hypercalciuria improved individualized medicine infancy innovation next generation sequencing novel novel strategies older patient open label pediatric patients prevent primary outcome rare genetic disorder recruit response skeletal standard care standard of care urinary

项目摘要

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.

项目总结/文摘