Targeting the vitamin D receptor for the treatment of rare diseases induced by calcitriosis – VARaD

High circulating levels of vitamin D (calcitriosis) lead to hypercalcemia, and are a hallmark of several rare refractory pediatric disorders. Among them, idiopathic infantile hypercalcemia type I (IIH1), induced by CYP24A1 biallelic mutations, is one of the most frequent diagnosed chronic calcitriosis. Current treatments are poorly efficient and greatly impact the development of children. Therefore, there is an urgent need to develop new therapies.

Vitamin D elicits its effect by binding to the Vitamin D Receptor (VDR), a member of the nuclear receptor superfamily. Interestingly, we have recently identified a vitamin D analog that acts as a VDR antagonist, and showed that it prevents vitamin D-induced hypercalcemia in mice, without any obvious side effect.

The objective of VARaD is to perform an extensive characterization of the effects of this VDR antagonist in Cyp24a1-null mice, a genetically engineered mouse model of IIH1, to further study its therapeutic activity and safety. We will determine blood biochemistry, renal functions and bone architecture in such mice treated or not with this compound, and performed transcriptomic analyses in various tissues involved in calcium homeostasis. Moreover, we established a collaboration with clinicians to obtain dermal fibroblasts from IIH1 patients’ skin biopsies to determine whether this antagonist normalizes calcitriol-induced VDR transcription in these cells.

The results gained from our study will provide important insights into the complex regulation of calcium homeostasis in vivo, and consolidate the therapeutic potency of the identified vitamin D analog for rare diseases induced by acute and chronic calcitriosis.