Jansen’s metaphyseal chondrodysplasia (JMC) is an ultra-rare disease of skeletal development and mineral ion balance. JMC is caused by mutations in the parathyroid hormone (PTH) receptor, which is present at particularly high levels in growth plates, bones and kidneys. The mutant PTH receptors of JMC are overactive, resulting in bone deformities, extremely short stature and chronic kidney disease, which often requires treatment by dialysis or kidney transplantation later in life. Other complications include premature closure of the spaces between the bones of the skull, leading to damage of cranial nerves and potential vision and hearing loss. Currently, there is no effective treatment for JMC. The lead collaborators have identified a peptide that can reduce the high baseline activity of the mutant PTH receptors. The goal of this project is to complete the preclinical studies necessary to enable clinical trials for JMC.
Scientific Synopsis
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), then were 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.
Lead Collaborators
Massachusetts General Hospital, Boston, MA
Thomas Gardella, Ph.D.
Harald Jueppner, M.D.
John Potts, Jr., M.D.
Public Health Impact
JMC is an ultra-rare genetic condition, with only about 30 cases identified since its first description in 1934. It is a progressive, debilitating condition with symptoms becoming apparent in early childhood. Patients undergo frequent surgical interventions and intensive physical and occupational therapy to realign bone and mitigate pain.
Outcomes
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.