A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia (JMC)

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药物物质的工艺，并生产了临床级(良好制造规范，GMP)配方，用于毒理学测试和临床试验。已对配方药物产品进行了使用中的测试和稳定性研究，并完成了成年大鼠的良好实验室操作规范(GLP)毒理学研究，以评估其安全性。该团队正在组织相关的法规文件，以编制研究新药(IND)申请，包括为NIH临床中心计划的试验计划的临床方案和操作计划。用于临床样本分析的生物分析方法的开发正在进行中，正在对幼年动物进行GLP毒理学研究，以支持在儿科患者中的最终试验。美国食品和药物管理局批准了甲状旁腺素-IA和JMC的孤儿药物和罕见儿科疾病称号，NIH临床中心正在进行JMC患者的自然病史研究。

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 a clinical-grade (Good Manufacturing Practice, GMP) formulation for toxicology testing and clinical trials. In-use testing and stability studies have been performed on the formulated drug product, and Good Laboratory Practice (GLP) toxicology studies in adult rats have been completed to assess its safety. The team is organizing relevant regulatory documentation to compile an Investigational New Drug (IND) application, including the clinical protocol and operations plans for the trial planned for the NIH Clinical Center. Bioanalytical methods development for clinical sample analysis is underway, and a GLP toxicology study in juvenile animals is being conducted to support eventual trials in pediatric patients. Orphan Drug and Rare Pediatric Disease Designations were granted by the FDA for PTH-IA and JMC, and a natural history study in JMC patients is ongoing at the NIH Clinical Center.