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Small molecule PTH1R inverse agonists as a therapy for Jansen's Metaphyseal Chondrodysplasia

Award Number: R21HD123465
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2026
PERIOD OF PERFORMANCE END DATE: 09/19/2028

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Small molecule PTH1R inverse agonists as a therapy for Jansen's Metaphyseal Chondrodysplasia - Abstract: Jansen Metaphyseal Chondrodysplasia (JMC) is an ultra-rare disorder caused by several different activating mutations, including H223R and T410R, in the parathyroid hormone (PTH)/PTH-related Peptide (PTHrP) receptor (PTH1R). This G protein-coupled receptor regulates calcium homeostasis via PTH and skeletal development and growth plate chondrocyte differentiation via PTHrP. Accordingly, JMC patients exhibit both calcium abnormalities (hypercalcemia, hypercalciuria, nephrocalcinosis) and severe skeletal dysplasia. We recently developed “humanized” T410R-PTH1R JMC model mice that recapitulate the severe growth plate abnormalities and mineral ion disturbances of JMC patients. Injection of these mice with a PTH inverse agonist (PTH-IA) peptide, which suppresses mutant receptor basal signaling, normalizes blood calcium levels, but not the growth plate defects caused by the T410R-JMC mutation. Our new mechanistic data suggest that T410R- PTH1R signals from intracellular compartments, which would not be efficiently accessed by a membrane- impermeable peptide. This led us to discover that a previously reported small molecule PTH1R antagonist, DS69910557 (DS699), functions as an inverse agonist at JMC mutant receptors in cells. We also found that a single s.c. injection or oral gavage of DS699 led to prolonged improvement in blood calcium levels in T410R- PTH1R mice, while twice-daily injection for three weeks improved, albeit modestly, growth plate morphology. Based on these proof-of-concept findings, we now propose to further define the extent that DS699 at varying doses can correct the defects in growth plate development and calcium homeostasis in T410R-PTH1R mice. We will also define the extent that DS699 specifically acts in osteoblasts and thus prevents the excessive accrural of bone mass in transgenic mice expressing H223R-PTH1R under the control of the collagen type I promoter. Finally, we will use cell-based biosensors to define the extent that JMC mutant PTH1Rs activate G proteins from the plasma membrane vs internalized subcellular compartments. These studies will help improve basic understanding of PTH1R biology and of how this GPCR can be targeted for improved therapeutic benefit.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $435,794 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	1	9/17/2026	NEW	$435,794
														Subtotal = $435,794

Grand Total All Awards = $435,794

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Small molecule PTH1R inverse agonists as a therapy for Jansen's Metaphyseal Chondrodysplasia

Award Number: R21HD123465

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2026

PERIOD OF PERFORMANCE END DATE: 09/19/2028

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