SFEBES2016 Poster Presentations Bone and Calcium (20 abstracts)
The calcilytic SHP635 rectifies hypocalcaemia and reduced parathyroid hormone concentrations in a mouse model for autosomal dominant hypocalcaemia type 1 (ADH1)
Fadil Hannan 1, , Valerie Babinsky 1 , Caroline Gorvin 1 , Tertius Hough 3 , Elizabeth Joynson 3 , Michelle Stewart 3 , Sara Wells 3 , Roger Cox 3 , Edward Nemeth 4 & Rajesh Thakker 1
1Radcliffe Department of Medicine, University of Oxford, Oxford, UK; 2Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK; 3MRC Harwell, Oxfordshire, UK; 4MetisMedica, Toronto, Canada.
Autosomal dominant hypocalcaemia type 1 (ADH1) is a systemic disorder of calcium homeostasis caused by gain-of-function mutations of the calcium-sensing receptor (CaSR). ADH1 may lead to symptomatic hypocalcaemia, inappropriately low parathyroid hormone (PTH) concentrations and hypercalciuria. Active vitamin D metabolites are the mainstay of treatment for symptomatic ADH1 patients, however their use predisposes to nephrocalcinosis, nephrolithiasis and renal impairment. Calcilytics are selective CaSR antagonists and represent a potential targeted therapy for ADH1. We have investigated SHP635, a calcilytic compound, for the treatment of ADH1 by in vivo studies involving a hypocalcaemic mouse model, known as Nuf, which harbours a gain-of-function CaSR mutation, Leu723Gln. WT and heterozygous-affected (Nuf/+) mice aged 20–28 weeks were used in accordance with UK Home Office legislation and project license restrictions. A dose-ranging study was undertaken by administering a single subcutaneous bolus of SHP635 at the following doses: 0, 1, 3, 10 and 30 mg/kg to n=4–6 Nuf/+ mice and measuring plasma PTH responses at 30 min post-dose. At baseline, Nuf/+ mice had significantly reduced PTH concentrations of 17±4 pmol/l compared to 68±19 pmol/l for WT mice (P<0.01). SHP635 significantly increased plasma PTH in a dose-dependent manner with the 30 mg/kg dose leading to a maximal PTH concentration of 371±30 pmol/l. To determine whether SHP635 may rectify the hypocalcaemia in Nuf/+ mice, a sub-maximal dose (25 mg/kg) was administered, and plasma adjusted-calcium concentrations measured at 0, 30 min, 1, 3 and 6 h post-dose. At baseline, Nuf/+ mice had significantly reduced adjusted-calcium concentrations of 1.87±0.03 mmol/l compared to 2.49±0.04 mmol/l for WT (P<0.01). SHP635 significantly increased plasma adjusted-calcium to a maximal concentration of 2.16±0.06 mmol/l (P<0.01) at 1hr post-dose, with values returning to baseline by 3 h. Our findings demonstrate that SHP635 rectifies the hypocalcaemia of Nuf mice, and indicate that this calcilytic is a potential treatment for ADH1.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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