A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia (JMC)

JMC是由G蛋白偶联甲状旁腺素受体1型(PTHR1)杂合性常染色体显性显性激活突变引起的，PTHR1在肾脏和骨骼，包括干骺端生长板中高度表达。PTHR1信号在骨的形成和长期生理中起着重要作用。在肾脏中，PTHR1激活PTHR1，刺激钙的重吸收和磷的排泄，并促进生物活性维生素D的产生；PTHR1信号因此起到平衡血液中矿物质离子的作用。在骨骼中，PTHR1信号的增加刺激骨基质的降解，并将钙和磷释放到血液中。JMC中PTHR1的结构性激活导致明显的骨骼异常，包括由于矿化不足导致的长骨矮小和弓形，以及慢性高钙血症和低磷血症。 主要合作者确定了JMC(H2 23R)的第一个也是最常见的PTHR1突变，并产生了相应的转基因小鼠模型(C1HR)，概括了JMC的一些骨骼表型。他们还通过体外研究确定了PTHR1反向激动剂配体可以抑制引起JMC的突变受体的高基础活性。这些基于甲状旁腺素或甲状旁腺素相关蛋白(PTHrP)片段的反向激动剂随后在C1HR小鼠体内进行了测试。其中一种甲状旁腺素反向激动剂(PTH-IA)被发现显著改善突变小鼠的骨和矿物质离子缺陷，支持PTH-IA可以作为JMC治疗的假设。 TRND科学家发起了一项临床前开发活动，以推动PTH-IA候选药物进入临床评估。该团队标准化了制造PTH-IA药物物质的过程，并已开始开发一种临床配方，供患者使用。生物分析方法已经开发出来，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，以允许在患者身上进行临床试验，计划在NIH临床中心进行。

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 begun to develop a clinical formulation 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.