A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia (JMC)

Jansens 干骺端软骨发育不良 (JMC) 患者的治疗方法

• 批准号: 10685888
• 负责人: Elizabeth Ottinger
• 金额: $ 396.65万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685888
• 关键词: Agonist; Blindness; Blood; Bone Matrix; Chronic; Chronic Kidney Failure; Clinical; Clinical Trials; Coupled; Cranial Nerves; Defect; Deformity; Dialysis procedure; Documentation; Epiphysial cartilage; Equilibrium; Formulation; GTP-Binding Proteins; Generations; Goals; Hormone Receptor; Hypercalcemia; Hypophosphatemia; In Vitro; Investigational New Drug Application; Ions; Kidney; Kidney Transplantation; Lead; Life; Ligands; Metaphyseal chondrodysplasia; Methods; Minerals; Mus; Mutant Strains Mice; Mutation; Natural History; PTH gene; Parathyroid Hormone Receptor; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Physiology; Play; Process; Rare Diseases; Role; Safety; Scientist; Signal Transduction; Skeletal Development; Standardization; Testing; Therapeutics for Rare and Neglected Diseases; Toxicology; Transgenic Mice; United States National Institutes of Health; Vitamin D; base; bone; calcium excretion; calcium phosphate; clinical center; cranium; effective therapy; hearing impairment; improved; in vivo evaluation; inorganic phosphate; long bone; mouse model; mutant; parathyroid hormone-related protein; preclinical development; preclinical study; premature; receptor; research clinical testing; skeletal; skeletal abnormality

JMC is caused by heterozygous, autosomal-dominant activating mutations in the G protein-coupled PTH receptor type 1 (PTHR1), which is highly expressed in kidney and bone, including the metaphyseal growth plates. PTHR1 signaling plays a role in the formation and long-term physiology of bone. In the kidney, PTH activates the PTHR1, stimulating the reabsorption of calcium and excretion of phosphate, and enhancing the generation of biologically active vitamin D; PTHR1 signaling thus acts to balance mineral ions in the blood. In bone, increased PTHR1 signaling stimulates the degradation of the bone matrix and the release of calcium and phosphate into the blood. Constitutive activation of the PTHR1 in JMC leads to marked skeletal abnormalities, including short stature and bowing of the long bones due to hypomineralization, as well as chronic hypercalcemia and hypophosphatemia. The lead collaborators identified the first, and most frequent, PTHR1 mutation of JMC (H223R) and generated a corresponding transgenic mouse model (C1HR) recapitulating some of the JMC skeletal phenotype. They also identified through in vitro studies PTHR1 inverse agonist ligands that can suppress the high basal activity of the mutant receptors causing JMC. These inverse agonists, based on fragments of PTH or the PTH-related protein (PTHrP), were then tested in vivo in the C1HR mouse. One of these PTH inverse agonists (PTH-IA) was found to significantly improve the bone and mineral ion defects in the mutant mice, supporting the hypothesis that a PTH-IA could be developed as a therapy for JMC. TRND scientists initiated a preclinical development campaign to advance the PTH-IA candidate to clinical evaluation. The team standardized a process to manufacture PTH-IA drug substance and has produced GMP material for toxicology testing and clinical trials. A clinical formulation has been developed and drug product will be formulated soon for administration to patients. Bioanalytical methods have been developed, and toxicology studies are ongoing to determine safety. Completion of these studies will support submission of an Investigational New Drug (IND) application to allow clinical trials in patients, planned to be conducted at the NIH Clinical Center. Efforts to organize the regulatory documentation and compile an IND application have begun and is expected to be filed in 2023. A patient natural history study has been initiated at the NIH Clinical Center and is currently ongoing.

JMC是由G蛋白偶联PTH受体1型（PTHR 1）中的杂合常染色体显性激活突变引起的，PTHR 1在肾脏和骨骼（包括干骺端生长板）中高度表达。PTHR 1信号传导在骨的形成和长期生理学中起作用。在肾脏中，PTH激活PTHR 1，刺激钙的重吸收和磷酸盐的排泄，并增强生物活性维生素D的产生; PTHR 1信号传导因此起到平衡血液中矿物质离子的作用。在骨中，增加的PTHR 1信号刺激骨基质的降解以及钙和磷酸盐释放到血液中。JMC中PTHR 1的组成性激活会导致明显的骨骼异常，包括身材矮小和由于矿化不足而导致的长骨弯曲，以及慢性高钙血症和低磷血症。 主要合作者确定了JMC的第一个也是最常见的PTHR 1突变（H223 R），并产生了相应的转基因小鼠模型（C1 HR），重现了一些JMC骨骼表型。他们还通过体外研究鉴定了PTHR 1反向激动剂配体，其可以抑制引起JMC的突变受体的高基础活性。然后在C1 HR小鼠体内测试基于PTH或PTH相关蛋白（PTHrP）片段的这些反向激动剂。发现这些PTH反向激动剂之一（PTH-IA）显著改善突变小鼠中的骨和矿物质离子缺陷，支持PTH-IA可以被开发为JMC的疗法的假设。 TRND科学家发起了一项临床前开发活动，以推进PTH-IA候选药物的临床评价。该团队标准化了生产PTH-IA原料药的工艺，并生产了用于毒理学测试和临床试验的GMP材料。已开发出临床制剂，不久将配制制剂用于患者给药。生物分析方法已经开发，毒理学研究正在进行中，以确定安全性。完成这些研究将支持提交研究性新药（IND）申请，以允许计划在NIH临床中心进行的患者临床试验。组织监管文件和编写IND申请的工作已经开始，预计将于2023年提交。 NIH临床中心已启动患者自然史研究，目前正在进行中。