A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia (JMC)

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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.