Comeglio Paolo, Guarnieri Giulia, Filippi Sandra, Cellai Ilaria, Acciai Gabriele, Holyer Ian, Zetterberg Fredrik, Leffler Hakon, Kahl-Knutson Barbro, Sarchielli Erica, Morelli Annamaria, Maggi Mario, Slack Robert J, Vignozzi Linda
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Front Pharmacol. 2024 Jul 31;15:1430109. doi: 10.3389/fphar.2024.1430109. eCollection 2024.
Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human K = 25 nM; rabbit K = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH).
Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin dosed therapeutically 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson's trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression.
Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease.
Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100 mg that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.
半乳糖凝集素-3是一种促纤维化的β-半乳糖苷结合凝集素，在纤维化肝脏中高度表达，并与肝纤维化有关。Selvigaltin（以前称为GB1211）是一种新型口服活性半乳糖凝集素-3小分子抑制剂，对半乳糖凝集素-3具有高亲和力（人K = 25 nM；兔K = 12 nM），在兔和人中具有高口服生物利用度。在本研究中，在代谢相关脂肪性肝炎（MASH）的高脂饮食（HFD）兔模型中研究了Selvigaltin的疗效。
雄性新西兰白兔在温度和湿度控制的房间内，在标准条件下单独饲养，光照/黑暗周期为12小时。在常规饮食（RD）1周后，将兔子随机分配到不同组8周或12周：RD/赋形剂、RD/Selvigaltin、HFD（8周）、HFD/赋形剂和HFD/Selvigaltin（0.3、1.0、5.0或30 mg/kg Selvigaltin与赋形剂/ Selvigaltin，从第9周或第12周开始每周治疗给药5天）。通过血液代谢标志物、组织形态学评估[油红O、吉姆萨、马森三色染色、苦味酸天狼星红（PSR）和二次谐波产生（SHG）]以及mRNA和蛋白质表达来测量肝脏炎症、脂肪变性、气球样变和纤维化。
从RD组到HFD/赋形剂组，脂肪变性、炎症、气球样变和纤维化均增加。通过免疫组织化学和mRNA分析测量，Selvigaltin通过显著降低肝脏中的半乳糖凝集素-3水平证明了靶点参与。Selvigaltin剂量依赖性地降低肝功能生物标志物（AST、ALT、胆红素）、炎症（细胞灶）和纤维化（PSR、SHG），以及降低几种关键炎症和纤维化生物标志物（如IL6、TGFβ3、SNAI2、胶原蛋白）的mRNA和蛋白质表达。1.0或5.0 mg/kg的剂量在大多数生物学终点上显示出一致的疗效，支持目前正在肝病研究中研究的Selvigaltin临床剂量。
在MASH的HFD兔模型中，Selvigaltin治疗给药4周后，以剂量依赖性方式显著降低肝脏炎症和纤维化。这些数据支持在肝硬化临床研究中已显示可降低关键肝脏生物标志物的100 mg人体Selvigaltin剂量。
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