Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer
Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer
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DOI：
10.1161/01.cir.0000091401.26280.a0
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发表时间：
2003-10-28
期刊：
影响因子：
37.8
通讯作者：
Schwaiger, M
中科院分区：
文献类型：
--
作者：
Bengel, FM;Anton, M;Schwaiger, M
背景-报告基因表达的放射性核素成像可能对临床心脏基因治疗的无创监测有用。然而，到目前为止，经验仅限于小动物。方法和结果-为了评估临床应用的可行性，在局部心肌内注射对照腺病毒或携带疱疹病毒胸苷激酶报告基因（HSV1-tk）的腺病毒2天后，用常规正电子发射断层扫描（PET）对猪进行了研究。用[N-13]氨定量心肌血流量。随后，在2小时内评估报告底物[I-124]-2'-氟-2'-脱氧-5-碘-1- β -d -阿拉伯-呋喃嘧啶（FIAU）的动力学。感染表达HSV1-tk的腺病毒的区域在注射后的前30分钟内FIAU保留率显著升高。在随后的时间里，观察到冲洗，保留与感染对照病毒或远端心肌的区域没有什么不同。早期体内FIAU摄取与安乐死后报告基因产物的离体图像、放射自显影和免疫组织化学相关。心肌内注射两种腺病毒后，心肌血流量较边远地区轻度升高，符合局部炎症的组织学征象。结论-应用临床PET方法、放射性碘化报告探针FIAU和HSV1-tk报告基因，在体内量化局部心肌转基因表达是可行的。特异性初始摄取后的放射性外溢在以前的肿瘤研究中没有观察到，这表明核苷代谢的组织特异性差异影响报告探针动力学。通过将报告基因表达与其他生物学参数（如心肌血流量）共登记，PET允许对心脏基因转移及其功能相关物的成功进行无创表征。
Background - Radionuclide imaging of reporter gene expression may be useful for noninvasive monitoring of clinical cardiac gene therapy. Experience until now, however, has been limited to small animals.Methods and Results - To evaluate feasibility in a clinically applicable setting, pigs were studied by conventional positron emission tomography (PET) 2 days after regional intramyocardial injection of control adenovirus or adenovirus carrying herpesviral thymidine kinase reporter gene (HSV1-tk). Myocardial blood flow was quantified by use of [N-13] ammonia. Subsequently, kinetics of the reporter substrate [I-124]-2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabino-furanosyluracil (FIAU) were assessed over a period of 2 hours. Areas infected with adenovirus expressing HSV1-tk showed significantly elevated FIAU retention during the first 30 minutes after injection. At later times, washout was observed, and retention was not different from that in areas infected with control virus or remote myocardium. Early in vivo FIAU uptake correlated with ex vivo images, autoradiography, and immunohistochemistry for reporter gene product after euthanasia. After intramyocardial injection of both adenoviruses, myocardial blood flow was mildly elevated compared with that in remote areas, consistent with histological signs of regional inflammation.Conclusions - In vivo quantification of regional myocardial transgene expression is feasible with clinical PET methodology, the radioiodinated reporter probe FIAU, and the HSV1-tk reporter gene. Radioactivity efflux after specific initial uptake was not observed previously in tumor studies, suggesting that tissue-specific differences in nucleoside metabolism influence reporter probe kinetics. By coregistering reporter gene expression with additional biological parameters such as myocardial blood flow, PET allows for noninvasive characterization of the success of cardiac gene transfer along with its functional correlates.