School of Biotechnology, Dublin City University, Dublin, Ireland; National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
School of Biotechnology, Dublin City University, Dublin, Ireland; National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
Vascul Pharmacol. 2021 Dec;141:106919. doi: 10.1016/j.vph.2021.106919. Epub 2021 Sep 25.
The Angiopoietin-1/2 system is an opportune target for therapeutic intervention in a wide range of vascular pathologies, particularly through its association with endothelium. The complex multi-domain structure of native human Angiopoietin-1 has hindered its widespread applicability as a therapeutic agent, prompting the search for alternative approaches to mimicking the Ang1:Tie2 signalling axis; a system with highly complex patterns of regulation involving multiple structurally similar molecules. An engineered variant, Cartilage Oligomeric Matrix Protein - Angiopoietin-1 (COMP-Ang1), has been demonstrated to overcome the limitations of the native molecule and activate the Tie2 pathway with several fold greater potency than Ang1, both in vitro and in vivo. The therapeutic efficacy of COMP-Ang1, at both the vascular and systemic levels, is evident from multiple studies. Beneficial impacts on skeletal muscle regeneration, wound healing and angiogenesis have been reported alongside renoprotective, anti-hypertensive and anti-inflammatory effects. COMP-Ang1 has also demonstrated synergy with other compounds to heighten bone repair, has been leveraged for potential use as a co-therapeutic for enhanced targeted cancer treatment, and has received considerable attention as an anti-leakage agent for microvascular diseases like diabetic retinopathy. This review examines the vascular Angiopoietin:Tie2 signalling mechanism, evaluates the potential therapeutic merits of engineered COMP-Ang1 in both vascular and systemic contexts, and addresses the inherent translational challenges in moving this potential therapeutic from bench-to-bedside.
血管生成素 1/2 系统是治疗多种血管病变的理想靶点，特别是通过与内皮细胞的关联。天然人血管生成素 1 的复杂多结构域结构限制了其作为治疗剂的广泛适用性，促使人们寻找替代方法来模拟 Ang1:Tie2 信号轴；这是一个具有高度复杂调控模式的系统，涉及多种结构相似的分子。一种工程变体，软骨寡聚基质蛋白-血管生成素 1（COMP-Ang1）已被证明克服了天然分子的局限性，并以比 Ang1 高几倍的效力激活 Tie2 途径，无论是在体外还是体内。COMP-Ang1 在血管和全身水平的治疗效果已在多项研究中得到证实。已报道其对骨骼肌再生、伤口愈合和血管生成的有益影响，以及肾保护、抗高血压和抗炎作用。COMP-Ang1 还与其他化合物具有协同作用，可增强骨修复，已被利用作为增强靶向癌症治疗的辅助治疗，并且作为治疗糖尿病性视网膜病变等微血管疾病的抗渗漏剂引起了广泛关注。本文综述了血管生成素 1/Tie2 信号机制，评估了工程化 COMP-Ang1 在血管和全身背景下的潜在治疗价值，并探讨了将这种潜在治疗方法从实验室转移到临床应用所面临的固有转化挑战。
