COLON

Angiogenesis blockade as a new therapeutic approach to experimental colitis

Silvio Danese¹, Miquel Sans², David M Spencer³, Ivy Beck⁴, Fernando Doñate⁴, Marian L Plunkett⁴, Carol de la Motte⁵, Raymond Redline⁶, David E Shaw⁷, Alan D Levine³, Andrew P Mazar⁴, Claudio Fiocchi⁵

¹ Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano, Milan, Italy
² Department of Gastroenterology, Hospital Clinic i Provincial/ IDIBAPS, CIBER-EHD, Barcelona, Spain
³ Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
⁴ Attenuon, LLC, San Diego, California, USA
⁵ Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
⁶ Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
⁷ DE Shaw Research and Development, New York, New York, USA

Correspondence to:
Dr S Danese
Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano, Milan 20089, Italy; sdanese{at}hotmail.com

Background: Neoangiogenesis is a critical component of chronic inflammatory disorders. Inhibition of angiogenesis is an effective treatment in animal models of inflammation, but has not been tested in experimental colitis.

Aim: To investigate the effect of ATN-161, an anti-angiogenic compound, on the course of experimental murine colitis.

Method: Interleukin 10-deficient (IL10^–/–) mice and wild-type mice were kept in ultra-barrier facilities (UBF) or conventional housing, and used for experimental conditions. Dextran sodium sulphate (DSS)-treated mice were used as a model of acute colitis. Mice were treated with ATN-161 or its scrambled peptide ATN-163. Mucosal neoangiogenesis and mean vascular density (MVD) were assessed by CD31 staining. A Disease Activity Index (DAI) was determined, and the severity of colitis was determined by a histological score. Colonic cytokine production was measured by ELISA, and lamina propria mononuclear cell proliferation by thymidine incorporation.

Result: MVD increased in parallel with disease progression in IL10^–/– mice kept in conventional housing, but not in IL10^–/– mice kept in UBF. Angiogenesis also occurred in DSS-treated animals. IL10^–/– mice with established disease treated with ATN-161, but not with ATN-163, showed a significant and progressive decrease in DAI. The histological colitis score was significantly lower in ATN-161-treated mice than in scrambled peptide-treated mice. Inhibition of angiogenesis was confirmed by a significant decrease of MVD in ATN-161-treated mice than in ATN-163-treated mice. No therapeutic effects were observed in the DSS model of colitis. ATN-161 showed no direct immunomodulatory activity in vitro.

Conclusion: Active angiogenesis occurs in the gut of IL10^–/– and DSS-treated colitic mice and parallels disease progression. ATN-161 effectively decreases angiogenesis as well as clinical severity and histological inflammation in IL10^–/– mice but not in the DDS model of inflammatory bowel disease (IBD). The results provide the rational basis for considering anti-angiogenic strategies in the treatment of IBD in humans.

Abbreviations: DAI, Disease Activity Index; DSS, dextran sodium sulphate; IBD, inflammatory bowel disease; IL, interleukin; IP, intraperitoneal; LPMC, lamina propria mononuclear cells; LPS, lipopolysaccharide; MVD, mean vascular density; PBS, phosphate-buffered saline; UBF, ultra-barrier facility; VEGF, vascular endothelial growth factor; WT, wild type

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