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A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease

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A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease biomedicines Review Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease Shinya Ashizuka 1,* , Toshihiro Kita 2 , Haruhiko Inatsu 1 and Kazuo Kitamura 2 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan; [email protected] 2 Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan; [email protected] (T.K.); [email protected] (K.K.) * Correspondence: [email protected] Abstract: Adrenomedullin (AM) is a bioactive peptide with various physiological functions, includ- ing vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic re- generation and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn’s disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment. Citation: Ashizuka, S.; Kita, T.; Keywords: adrenomedullin; inflammatory bowel disease; ulcerative colitis; Crohn’s disease; transla- Inatsu, H.; Kitamura, K. tional research; drug discovery research Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease. Biomedicines 2021, 9, 1068. https:// 1. Introduction doi.org/10.3390/biomedicines9081068 Ulcerative colitis (UC) and Crohn’s disease (CD) are the most common types of chronic inflammatory bowel disease (IBD). The number of people with IBD worldwide reached Academic Editor: Giovanni Pallio over 6.8 million in 2017 [1]. The cause of IBD is unknown but is thought to be caused by abnormalities in intestinal immunity, a genetic predisposition, and environmental factors, Received: 28 July 2021 such as diet and intestinal microflora. Accepted: 20 August 2021 Although there is no cure for IBD, there have been remarkable therapeutic develop- Published: 23 August 2021 ments that contribute to the induction and maintenance of remission over the past 20 years, including anti-TNF-alpha antibodies, tacrolimus, anti-IL-12/23p40 antibodies, Janus kinase Publisher’s Note: MDPI stays neutral (JAK) inhibitors, and integrin inhibitors. While these drugs have shown excellent efficacy, with regard to jurisdictional claims in published maps and institutional affil- they also negatively affect patients’ immune systems, leading some patients to develop iations. infections and malignant lymphomas. Severe infections such as tuberculosis and Pneumocystis pneumonia require serious attention, particularly in elderly patients and patients with underlying diseases, such as diabetes mellitus. Further, the above treatments demonstrate a diminishing therapeutic response, as they are immunogenic and targets of anti-drug antibodies. Therefore, the de- Copyright: © 2021 by the authors. velopment of new therapeutic agents for IBD requires efficacy, safety, and immunogenicity. Licensee MDPI, Basel, Switzerland. Adrenomedullin (AM), an endogenous vasodilatory peptide, was isolated from hu- This article is an open access article man pheochromocytoma by Kitamura et al. in 1993 [2]. AM was initially studied as a distributed under the terms and conditions of the Creative Commons circulatory agonist but was later found to promote angiogenesis, organ protection, and Attribution (CC BY) license (https:// anti-inflammatory immune activity. AM is also widely expressed in the gastrointestinal creativecommons.org/licenses/by/ tract epithelia and effectively treats gastric ulcers and enteritis in animal models. Therefore, 4.0/). we began translational research on the clinical application of AM in IBD [3]. Biomedicines 2021, 9, 1068. https://doi.org/10.3390/biomedicines9081068 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 11 Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 11 Biomedicines 2021, 9, 1068 2 of 12 epithelia and effectively treats gastric ulcers and enteritis in animal models. Therefore, we epithelia and effectively treats gastric ulcers and enteritis in animal models. Therefore, we began translational research on the clinical application of AM in IBD [3]. began translational research on the clinical application of AM in IBD [3]. Since AM is an endogenous bioactive peptide, it has low immunogenicity, is consid- Since AM is an endogenous bioactive peptide, it has low immunogenicity, is consid- ered relatively safe, and is expected to be developed into a novel IBD treatment. In this ered relativelyrelatively safe,safe, andand isis expectedexpected toto bebe developeddeveloped intointo aa novelnovel IBDIBD treatment.treatment. InIn thisthis article, we review the basics of AM research findings, including its effects on enteritis in article, we review thethe basicsbasics ofof AMAM researchresearch findings,findings, includingincluding itsits effectseffects onon enteritisenteritis inin animal models, and present the current status and potential of clinical research findings animal models,models, andand present present the the current current status status and and potential potential of clinicalof clinical research research findings findings for for IBD patients. IBDfor IBD patients. patients. 2. Structure and Biosynthesis of Adrenomedullin 2. Structure and Biosynthesis of Adrenomedullin AM is composed of 52 amino acids [2] and has a ring structure consisting of six amino AM is is composed composed of of 52 52 amino amino acids acids [2] [and2] and has hasa ring a structure ring structure consisting consisting of six amino of six acids and a C-terminal amide structure (Figure 1). These two structural features are essen- aminoacids and acids a C-terminal and a C-terminal amide structure amide structure (Figure 1). (Figure These1 ).two These structural two structural features are features essen- tial for their biological activity. It also shares homology with calcitonin gene-related pep- aretial essentialfor their biological for their biologicalactivity. It activity.also shares Italso homology shares with homology calcitonin with gene-related calcitonin gene- pep- tide (CGRP), amylin, and adrenomedullin 2/intermedin (AM2/IMD) to form the calcitonin relatedtide (CGRP), peptide amylin, (CGRP), and amylin, adrenomedullin and adrenomedullin 2/intermedin 2/intermedin (AM2/IMD) to (AM2/IMD) form the calcitonin to form peptide superfamily. thepeptide calcitonin superfamily. peptide superfamily. Figure 1. Amino-acid sequence of human Adrenomedullin. Figure 1.1. Amino-acid sequence of human Adrenomedullin. AM is widely expressed throughout the blood vessels, heart, lungs, kidneys, and gas- AM is widely expressed throughout the blood vessels, heart, lungs, kidneys, and gas- trointestinal tract and is highly concentrated in the adrenal medulla. The pro-adrenome- trointestinaltrointestinal tracttract and and is is highly highly concentrated concentrated in thein the adrenal adrenal medulla. medulla. The The pro-adrenomedullin pro-adrenome- dullin N-terminal 20 peptide (PAMP) has a shorter duration of antihypertensive activity N-terminaldullin N-terminal 20 peptide 20 peptide (PAMP) (PAMP) has a shorter has a duration shorter duration of antihypertensive of antihypertensive activity than activity AM than AM and cooperatively regulates blood circulation with AM (Figure 2) [4]. Although andthancooperatively AM and cooperatively regulates regulates blood circulation blood circulation with AM with (Figure AM2 )[(Figure4]. Although 2) [4]. Although mid re- mid regional pro-adrenomedullin (MR-pro ADM) has no biological activity, it has been gionalmid regional pro-adrenomedullin pro-adrenomedullin (MR-pro (MR-pro ADM) has ADM) no biological has no biological activity, it activity, has been it attracting has been attracting attention as a biomarker for the prognosis of heart failure [5], myocardial in- attentionattracting asattention a biomarker as a biomarker for the prognosis for the ofprognosis heart failure of heart [5], failure myocardial [5], myocardial infarction [in-5], farction [5], community-acquired pneumonia [6], septic shock [7], and COVID-19 [8,9]. community-acquiredfarction [5], community-acquired pneumonia [pneumonia6], septic shock [6], septic [7], and shock COVID-19 [7], and [8 COVID-19,9]. [8,9]. Figure 2. Schematic representations of the processingprocessing of AM, MR-proAM, andand PAMPPAMP fromfrom proAM. proAM.Figure 2. Schematic representations of the processing of AM, MR-proAM, and PAMP from 3.proAM. Adrenomedullin Receptors 3. AdrenomedullinThe AM receptor Receptors consists of a complex of calcitonin receptor-like receptors (CRLR; 3. Adrenomedullin Receptors a seven-transmembraneThe AM receptor consists G protein of a complex receptor) of andcalcitonin a receptor receptor-like activity-modifying receptors (CRLR; protein a The AM receptor consists of a complex of calcitonin receptor-like receptors (CRLR; a (RAMP;seven-transmembrane a single transmembrane G protein receptor). receptor) Thereand a are receptor three
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