A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia

Jansens 干骺端软骨发育不良患者的治疗

• 批准号: 10253937
• 负责人: Elizabeth Ottinger
• 金额: $ 186.62万
• 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/10253937
• 关键词: Agonist; Biological; Blindness; Blood; Bone Matrix; Chronic; Chronic Kidney Failure; Clinical Trials; Coupled; Cranial Nerves; Defect; Deformity; Development; Dialysis procedure; Drug Formulations; Epiphysial cartilage; Equilibrium; 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; PTH gene; Parathyroid Hormone Receptor; Patients; Peptides; Phenotype; Physiology; Play; Rare Diseases; Role; Scientist; Signal Transduction; Skeletal Development; Therapeutics for Rare and Neglected Diseases; Toxicology; Transgenic Mice; Vitamin D; base; bone; calcium excretion; calcium phosphate; cranium; effective therapy; hearing impairment; improved; in vivo evaluation; inorganic phosphate; long bone; manufacturing scale-up; 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 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.

JMC是由G蛋白偶联PTH受体1型（PTHR1）的杂合子、常染色体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作用。在肾脏中，PTH激活PTHR1，刺激钙的重吸收和磷酸盐的排泄，促进生物活性维生素D的生成；因此，PTHR1信号可以平衡血液中的矿物质离子。在骨中，PTHR1信号的增加刺激骨基质的降解和钙和磷酸盐释放到血液中。JMC中PTHR1的组成性激活导致明显的骨骼异常，包括由于低矿化导致的身材矮小和长骨弯曲，以及慢性高钙血症和低磷血症。