Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial
Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial
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DOI：
10.1016/j.omtm.2020.05.030
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发表时间：
2020-09-11
影响因子：
4.7
通讯作者：
Gan, Li-Ming
中科院分区：
文献类型：
--
作者：
Anttila, Vesa;Saraste, Antti;Gan, Li-Ming
治疗性血管生成可能改善接受外科血管重建术的冠心病患者的预后。血管生成因子可以促进血管生长和再生缺血但存活的心肌区域。以往使用DNA或病毒载体进行血管内皮生长因子A(VEGF-A)基因治疗的临床试验证明是安全的，但不是有效的。AZD8601是在生物相容的柠檬酸缓冲盐水中配制的血管内皮生长因子-A(165)mRNA，针对高效表达血管内皮生长因子-A而进行了优化，天然免疫反应最小。EPICCURE是一项正在进行的随机、双盲、安慰剂对照研究，研究AZD8601在接受择期冠状动脉搭桥手术的中度左心功能减退(射血分数30%~50%)患者中的安全性。AZD8601 3 mg、30 mg或安慰剂作为30次心外膜注射，延长心脏停搏10分钟。使用定量O-15水正电子发射断层扫描(PET)成像(负荷心肌血流量2.3mL/g/min；静息心肌血流量0.6mL/g/min)针对每个患者的缺血但存活的心肌区域进行注射。与超声心动图、临床、功能和生物标记物测量相结合，O-15-water PET对局部和整体心肌血流量的改善是一种探索性的疗效结果。EPICCURE将高效率的交付与定量靶向和跟踪相结合，对血管生成血管生成的安全性和探索性有效性进行了强有力的评估(ClinicalTrials.gov：NCT03370887)。
Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A(165) mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30% 50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative O-15-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with O-15-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887).