SFEBES2022 Oral Communications Bone and Calcium (6 abstracts)
The AXT914 calcilytic compound increases plasma calcium and PTH in a mouse model for autosomal dominant hypocalcaemia type 1 (ADH1)
Kreepa Kooblall 1 , Fadil Hannan 2 , Mark Stevenson 1 , Kate Lines 1 , Xin Meng 2 , Michelle Stewart 3 , Sara Wells 3 , Jürg Gasser 4 & Rajesh Thakker 1
1Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, United Kingdom; 2Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom; 3MRC Harwell, Mary Lyon Centre, Harwell Science and Innovation Campus, Harwell, United Kingdom; 4Novartis Institutes for BioMedical Research, Department of Musculoskeletal Diseases, Novartis Campus St. Johann, Basel, Switzerland
Heterozygous germline gain-of-function mutations of the extracellular calcium-sensing receptor (CaSR), a G-protein coupled receptor (GPCR), result in autosomal dominant hypocalcaemia type 1 (ADH1), which may cause symptomatic hypocalcaemia with low circulating parathyroid hormone (PTH) concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, rectify the gain-of-function caused by CaSR mutations and are a potential targeted therapy for ADH1. However, calcilytic drugs are unavailable for clinical use and their effectiveness for the treatment of ADH1-associated hypocalcaemia is unclear. We investigated the orally active calcilytic AXT914, a quinazolinone derivative, for the treatment of ADH1 by in vitro and in vivo mouse studies of a heterozygous gain-of-function CaSR mutation, Leu723Gln, known as Nuf. Treatment of HEK293 cells stably expressing Nuf mutant (Gln723) CaSR with AXT914 concentrations ranging from 1-20nM decreased extracellular calcium-mediated intracellular calcium responses of the Nuf mutant CaSR in a concentration-dependent manner. Moreover, at 10nM, AXT914 successfully normalised the gain-of-function caused by the Nuf mutant CaSR. In vivo studies involving adult Nuf mice were performed in accordance with institutional welfare guidelines. A single 10 mg/kg dose of AXT914 or vehicle was administered by oral gavage to adult male and female Nuf mice. Nuf mice treated with AXT914 (n=7) had significant increases in plasma PTH concentrations at 30min post-dose (104±29 pmol/l vs. 23±4 pmol/l for vehicle-treated mice (n=6), P<0.05) and significant increases in plasma albumin-adjusted calcium at 120min post-dose (2.03±0.02 mmol/l vs. 1.84±0.02 mmol/l for vehicle-treated mice, P<0.001). AXT914 treatment did not alter plasma phosphate, magnesium, or creatinine concentrations. In summary, these studies demonstrate that AXT914 rectifies the gain-of-function caused by the Nuf mutant (Gln723) CaSR in vitro, and increases plasma calcium and PTH in Nuf mice in vivo. Thus, AXT914 represents a targeted therapy for clinical use in hypocalcaemia caused by ADH1.
Volume 86
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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