# PTH Inverse Agonists as Therapy for Jansen’s Disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $402,660

## Abstract

PROJECT SUMMARY/ABSTRACT
Jansen's Metaphyseal Chondrodysplasia (JMC) is a rare developmental disease caused by activating, gain-
of-function mutations in the PTH1R, the receptor for parathyroid hormone (PTH) and PTH-related peptide
(PTHrP). The PTH1R mutations lead to abnormal skeletal development resulting in severe, crippling bone
deformities, and extremely short stature. In addition, JMC patients develop chronic, often severe
hypercalcemia and hypercalciuria that contribute to development of chronic kidney disease (CKD) later in life,
necessitating kidney replacement therapy in older adults. There is currently no cure or effective treatment for
JMC, despite a clearly defined molecular target. We previously developed several PTH-PTHrP analogs that
show inverse agonism when tested in cells expressing different constitutively active PTH1Rs, including the
H223R-PTH1R mutant. Our extensive preliminary studies have shown that one inverse agonist, namely
L11,dW12,W23,Y36-PTHrP(7-36) (dTrp12-PTHrP(7-36)), reverses in vivo effects induced by the H223R-PTH1R
mutant expressed via the type I collagen promoter (Col1-H223R mice), thus reducing bone turnover and
cortical bone loss, and improving bone length. We now plan to provide further documentation that this PTH
analog, or a derivative thereof, can prevent the growth plate abnormalities, which occur in mice expressing
the H223R-PTH1R mutant in proliferating chondrocytes via the type II collagen promoter (Col2-H223R mice);
homozygous Col2-H223R mice are small, just like JMC patients, and it is plausible that pre- and/or post-natal
treatment with an inverse agonist will improve bone growth. We also propose developing transgenic mice
expressing the mutant PTH1R in proximal and distal tubules, and if necessary a “knock-in” JMC mouse, i.e. a
murine model mimicking all disease aspects. Besides correction of growth plate abnormalities in children
affected by JMC, it is conceivable that inverse agonists will prevent hypercalcemia and hypercalciuria in
pediatric and adult patients with activating PTH1R mutations, and thus nephrocalcinosis and CKD. Insights
into the mechanisms that reduce signaling at the mutant PTH1R may lead to effective approaches targeting
the wild-type PTH1R through additional peptide analogs or small molecules in patients with PTH- or PTHrP-
dependent hypercalcemia, or with secondary hyperparathyroidism due to CKD. In addition, our studies will
provide novel insights into growth plate, bone, and kidney physiology, and they will encourage searches for
inverse agonists at other disease-causing G protein-coupled receptor mutants.

## Key facts

- **NIH application ID:** 10200028
- **Project number:** 5R01DK113039-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** THOMAS J GARDELLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,660
- **Award type:** 5
- **Project period:** 2018-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200028

## Citation

> US National Institutes of Health, RePORTER application 10200028, PTH Inverse Agonists as Therapy for Jansen’s Disease (5R01DK113039-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200028. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*