A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia

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的组成性激活导致明显的骨骼异常，包括由于矿化不足引起的身材矮小和长骨弯曲，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的科学家们已经启动了一项临床前开发活动，以推进PTH-IA候选药物的临床评价。计划的活动包括开发生物分析方法，扩大制剂的生产和配制，以及支持研究性新药（IND）申请所需的毒理学研究。

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 have initiated a preclinical development campaign to advance the PTH-IA candidate to clinical evaluation. Planned activities include development of bioanalytical methods, scale-up manufacturing and formulation of the drug product, and the toxicology studies needed to support an Investigational New Drug (IND) application.