R&D, AptamiR Therapeutics, Inc, Naples, Florida, USA
R&D, AptamiR Therapeutics, Inc, Naples, Florida, USA.
BMJ Open Diabetes Res Care. 2020 Oct;8(1). doi: 10.1136/bmjdrc-2020-001478.
We previously demonstrated in primary cultures of human subcutaneous adipocytes and in a mouse model of diet-induced obesity that specific microRNA-22-3p antagomirs produce a significant reduction of fat mass and an improvement of several metabolic parameters. These effects are related to the activation of target genes such as , , , and involved in lipid catabolism, thermogenesis, insulin sensitivity and glucose homeostasis.
We now report a dedicated study exploring over the course of 3 months the metabolic and energetic effects of subcutaneous administration of our first miR-22-3p antagomir drug candidate (APT-110) in adult C57BL/6 male mice. Body composition, various blood parameters and energy expenditure were measured at several timepoints between week 12 and week 27 of age.
Weekly subcutaneous injections of APT-110 for 12 weeks produced a sustained increase of energy expenditure as early as day 11 of treatment, a significant fat mass reduction, but no change of appetite nor physical activity. Insulin sensitivity as well as circulating glucose, cholesterol and leptin were improved. There was a dramatic reduction of liver steatosis after 3 months of active treatment. RNA sequencing revealed an activation of lipid metabolism pathways in a tissue-specific manner.
These original findings suggest that microRNA-22-3p inhibition could lead to a potent treatment of fat accumulation, insulin resistance, and related complex metabolic disorders such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease.
我们之前在人皮下脂肪细胞的原代培养物和饮食诱导肥胖的小鼠模型中证明，特定的 microRNA-22-3p 反义寡核苷酸可显著减少脂肪量，并改善多种代谢参数。这些作用与激活靶基因有关，如参与脂代谢、产热、胰岛素敏感性和葡萄糖内稳态的 、 、 和 。
我们现在报告一项专门的研究，在成年 C57BL/6 雄性小鼠中，在 3 个月的时间内探索皮下给予我们的第一个 miR-22-3p 反义寡核苷酸药物候选物（APT-110）的代谢和能量效应。在 12 至 27 周龄期间的多个时间点测量身体成分、各种血液参数和能量消耗。
每周皮下注射 APT-110 12 周，早在治疗第 11 天就产生了持续的能量消耗增加，显著减少了脂肪量，但食欲和体力活动没有变化。胰岛素敏感性以及循环葡萄糖、胆固醇和瘦素得到改善。经过 3 个月的积极治疗，肝脏脂肪变性明显减少。RNA 测序显示脂质代谢途径在组织特异性激活。
这些原始发现表明，microRNA-22-3p 抑制可能导致脂肪堆积、胰岛素抵抗以及相关的复杂代谢紊乱（如肥胖、2 型糖尿病和非酒精性脂肪肝病）的有效治疗。
