Fuchs Shmuel, Dib Nabil, Cohen Barry M, Okubagzi Petros, Diethrich Edward B, Campbell Ann, Macko Jennifer, Kessler Paul D, Rasmussen Henrik S, Epstein Stephen E, Kornowski Ran
Cardiology Department, Rabin Medical Center, Petach-Tikva, Israel.
Catheter Cardiovasc Interv. 2006 Sep;68(3):372-8. doi: 10.1002/ccd.20859.
The experience with direct myocardial injection of adenovirus encoding angiogenic growth factor is limited to invasive surgical approach. Accordingly, we sought to evaluate, for the first time, in a randomized, double-blind, placebo-controlled, phase I pilot study the safety and feasibility of percutaneous catheter-based intramyocardial delivery of a replication-deficient adenovector encoding the 121-amino-acid isoform of vascular endothelial growth factor (AdVEGF121).
Ten "no-option" patients with severe coronary artery disease were randomized (2:1) to receive AdVEGF121 (4 x 10(10) pu) or placebo as fifteen 100 microL, evenly distributed, endomyocardial injections using a nonflouroscopic, 3-dimensional mapping and injection (NOGA) catheter-based system.
Injection procedure was successfully completed in all cases and was associated with no major adverse events. AdVEGF121 was considered potentially associated with a single serious adverse event of transient moderate fever. Elevated postprocedure CK and CK-MB fraction levels were recorded in two placebo-treated and three AdVEGF121-treated patients; all CK measured values were <1.5 times upper limit of normal. All adenoviral cultures (urine and throat swab) were negative 24-hr after dosing, and no significant changes in serial plasma VEGF levels were noted over time. At 12 months follow-up, no cancers, proliferative retinal changes, or significant abnormalities in hepatic, renal or hematological indices were observed.
Percutaneous, catheter-based AdVEGF121 intramyocardial injection is a practical, feasible, and potentially safe approach for intramyocardial gene transfer. A larger randomized, phase II efficacy study is warranted.
直接心肌注射编码血管生成生长因子的腺病毒的经验仅限于侵入性手术方法。因此，我们首次在一项随机、双盲、安慰剂对照的I期试点研究中，评估了经皮导管介导的心肌内递送编码血管内皮生长因子121个氨基酸异构体的复制缺陷腺病毒载体（AdVEGF121）的安全性和可行性。
10例患有严重冠状动脉疾病的“无其他选择”患者被随机分组（2:1），使用基于非荧光三维标测和注射（NOGA）导管系统，接受AdVEGF121（4×10¹⁰个病毒颗粒）或安慰剂，进行15次每次100微升、均匀分布的心内膜注射。
所有病例均成功完成注射过程，且未发生重大不良事件。AdVEGF121被认为可能与1例短暂中度发热的严重不良事件有关。在2例接受安慰剂治疗和3例接受AdVEGF121治疗的患者中记录到术后肌酸激酶（CK）和肌酸激酶同工酶MB（CK-MB）分数水平升高；所有CK测量值均<正常上限的1.5倍。给药后24小时，所有腺病毒培养物（尿液和咽拭子）均为阴性，且随时间推移，血浆VEGF水平无显著变化。在12个月的随访中，未观察到癌症、增殖性视网膜病变或肝、肾或血液学指标的明显异常。
经皮导管介导的AdVEGF121心肌内注射是一种实用、可行且潜在安全的心肌内基因转移方法。有必要进行更大规模的随机II期疗效研究。
