Endocrine Abstracts

Idiopathic Infantile Hypercalcemia (IIH) is a rare inborn form of severe vitamin D hypersensitivity, with an estimated incidence of 1:33.000 live birth and a high degree of misdiagnosis. Since the identification of CYP24A1 loss-of-function variants inducing IIH in 2011, over 41 pathogenic variants have been described, and represent the major genetic drivers of IIH¹. CYP24A1 encodes the main catalytic hydroxylase of the bioactive form of vitamin D (1,25D3). Upon binding to its nuclear receptor VDR, 1,25D3 regulates intestinal calcium absorption, renal calcium reabsorption and bone resorption, thus playing a key role in calcium homeostasis. IIH phenotype embraces a wide range of clinical features and the current therapeutic protocols, aimed to control long-lasting and recurrent hypercalcemic episodes, do not selectively target vitamin D signalling. In addition, long-term and high-dose regimens negatively impact patient’s quality of life, and a protracted administration is not always advisable. Thus, there is a significant unmet medical need for selective treatments for this metabolic disorder. We have shown that the VDR antagonist ZK168281 (ZK) normalizes VDR signaling and prevents 1.25D3-induced hypercalcemia in wild type mice, without any obvious side effect². To determine the therapeutic potency of ZK for IIH, we generated CYP24A1-null mice and showed that they recapitulate the human disease, including biochemical changes in mineral metabolism (e.g. hypercalcemia, hypercalciuria), renal abnormalities (e.g. nephrolithiasis, tubular fibrosis and glomerular injury), suppressed levels of parathyroid hormone and bone mineralization defects. Moreover, we demonstrated that serum calcium levels and renal calcium excretion fall back within physiological ranges in Cyp24a1-null mice treated for 2 weeks with ZK. In addition, we showed that this treatment improves nephrocalcinosis and renal fibrosis of Cyp24a1-null mice, highlighting the therapeutic potency of ZK. As little is known about the tissue-specific molecular events secondary to hypercalcemia induced by CYP24A1-deficiency, we performed a comparative genome-wide transcriptomic analysis in the key vitamin D target tissues, namely intestine, kidney and bone. In depth bio-informatic analysis revealed the key pathways involved in the disease, and importantly, we demonstrated that ZK normalizes these transcriptomic alterations of Cyp24a1-null mice. Thus, this compound, that selectively targets VDR, represents a potent and safe therapeutic option and opens new avenue for the treatment of refractory rare diseases secondary to hypervitaminosis-D.

References: 1. Schlingmann K.P. et al., (2011). N. Engl. J. Med, 365, 410 – 421.

2. Rovito D. et al., (2020). Nat Commun, 11(1):6249.