Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland.
Int J Mol Sci. 2022 Feb 15;23(4):2159. doi: 10.3390/ijms23042159.
Inflammatory bowel diseases (IBD) are chronic and relapsing gastrointestinal disorders, where a significant proportion of patients are unresponsive or lose response to traditional and currently used therapies. In the current study, we propose a new concept for anti-inflammatory treatment based on a selective acidic mammalian chitinase (AMCase) inhibitor. The functions of chitinases remain unclear, but they have been shown to be implicated in the pathology of various inflammatory disorders regarding the lung (asthma, idiopathic pulmonary fibrosis) and gastrointestinal tract (IBD and colon cancer). The aim of the study is to investigate the impact of AMCase inhibitor (OAT-177) on the dextran sulfate sodium (DSS)-induced models of colitis. In the short-term therapeutic protocol, OAT-177 given intragastrically in a 30 mg/kg dose, twice daily, produced a significant ( < 0.001) anti-inflammatory effect, as shown by the macroscopic score. Additionally, OAT-177 significantly decreased TNF-α mRNA levels and MPO activity compared to DSS-only treated mice. Intraperitoneal administration of OAT-177 at a dose of 50 mg/kg caused statistically relevant reduction of the colon length. In the long-term therapeutic protocol, OAT-177 given intragastrically in a dose of 30 mg/kg, twice daily, significantly improved colon length and body weight compared to DSS-induced colitis. This is the first study proving that AMCase inhibitors may have therapeutic potential in the treatment of IBD.
炎症性肠病（IBD）是一种慢性、复发性的胃肠道疾病，其中相当一部分患者对传统和目前使用的治疗方法没有反应或失去反应。在目前的研究中，我们提出了一种基于选择性酸性哺乳动物壳聚糖酶（AMCase）抑制剂的抗炎治疗新概念。壳聚糖酶的功能尚不清楚，但已表明它们与肺部（哮喘、特发性肺纤维化）和胃肠道（IBD 和结肠癌）的各种炎症性疾病的病理学有关。本研究旨在研究 AMCase 抑制剂（OAT-177）对葡聚糖硫酸钠（DSS）诱导的结肠炎模型的影响。在短期治疗方案中，OAT-177 以 30mg/kg 的剂量每天两次经胃内给药，表现出显著的抗炎作用（<0.001），如宏观评分所示。此外，与仅用 DSS 治疗的小鼠相比，OAT-177 显著降低了 TNF-α mRNA 水平和 MPO 活性。OAT-177 以 50mg/kg 的剂量腹腔给药可使结肠长度的统计学相关性降低。在长期治疗方案中，OAT-177 以 30mg/kg 的剂量每天两次经胃内给药，与 DSS 诱导的结肠炎相比，明显改善了结肠长度和体重。这是第一项证明 AMCase 抑制剂在治疗 IBD 方面可能具有治疗潜力的研究。
