Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043—a derivative of angiopoietin-like 3 (ANGPTL3)—as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin α₅β₁ on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial (NCT02491281; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial (NCT04864392) in patients with knee OA.

骨关节炎（OA）是一种常见的、使人衰弱的慢性疾病，迄今为止还没有批准缓解疾病的药物。我们通过对人间充质干细胞进行表型筛选，发现 LNA043（血管生成素样 3 (ANGPTL3) 的衍生物）是一种有效的软骨形成诱导剂。我们发现 LNA043 在体外促进软骨形成和软骨基质合成，并在临床前 OA 和体内软骨损伤模型中再生透明关节软骨。LNA043 至少部分通过与间充质干细胞和软骨细胞上的纤连蛋白受体、整合素 α ₅ β ₁结合来发挥这些作用。在一项首次人体试验（1 期）、随机、双盲、安慰剂对照、单剂量递增、单中心试验（NCT02491281；由诺华制药赞助）中，28 名膝关节 OA 患者关节内注射了全膝关节置换术前 2 小时、7 天或 21 天使用 LNA043 或安慰剂（3:1 比例）。LNA043 达到了主要安全终点，并显示出较短的血清药代动力学、软骨渗透性和缺乏免疫原性（次要终点）。软骨的事后转录组学分析显示，单次 LNA043 注射可在至少 21 天内逆转 OA 转录组特征，诱导透明软骨基质成分和合成代谢信号通路的表达，同时抑制 OA 进展的介质。LNA043 是一种新型缓解 OA 疾病的候选药物，目前正在膝关节 OA 患者中进行 2b 期试验 (NCT04864392)。