title: Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease.
abstract: Deficiency in 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)) has been suggested as an important environmental factor for immuno-mediated disorders including inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis, both characterized by chronic intestinal inflammation. Administration of vitamin D receptor (VDR) agonists can ameliorate spontaneous and induced animal models of colitis, but hypercalcemia is a dose-limiting adverse event. Previous work in our laboratory has identified 1alpha,25(OH)(2)-16-ene-20-cyclopropyl-vitamin D(3) (BXL-62) as a potent anti-inflammatory VDR agonist with a low calcemic activity. In the present study, we confirm the marked anti-inflammatory properties of BXL-62 and show its capacity to induce VDR primary response genes, like CYP24A1 and CAMP, at lower concentrations than 1,25D(3), in PBMCs from IBD patients. Its higher anti-inflammatory potency compared to 1,25D(3) was demonstrated by the significantly more potent inhibition in PBMCs and in lymphocyte-enriched lamina propria mononuclear cells of the pro-inflammatory cytokines TNF-alpha, IL-12/23p40, IL-6 and IFN-gamma, both at mRNA and protein level. The therapeutic efficacy of intra-rectal administration of BXL-62 in experimental IBD is shown by its beneficial effects, significantly higher than 1,25D(3), to induce recovery of clinical symptoms of colitis at normocalcemic doses in mice undergoing dextran sodium sulfate-induced colitis. These results confirm the therapeutic efficacy of VDR agonists in experimental colitis, and suggest BXL-62 as a promising compound for IBD treatment.
authors.affiliation: BioXell S.p.A, Milan, Italy. g.laverny@gmail.com
authors.forename: Gilles
authors.initials: G
authors.lastname: Laverny
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Penna
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.forename: Carmen
authors.initials: C
authors.lastname: Correale
authors.forename: Manuela
authors.initials: M
authors.lastname: Nebuloni
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000188:drug therapy; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy; D005260:Female; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009092:Mucous Membrane / Q000187:drug effects / Q000473:pathology; D018167:Receptors, Calcitriol / Q000819:agonists*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D018167:Receptors, Calcitriol; D002117:Calcitriol