A pharmacokinetic analysis of molecular cardiac surgery with recirculation mediated delivery of βARKct gene therapy: developing a quantitative definition of the therapeutic window.
A pharmacokinetic analysis of molecular cardiac surgery with recirculation mediated delivery of βARKct gene therapy: developing a quantitative definition of the therapeutic window.
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DOI：
10.1016/j.cardfail.2011.03.011
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发表时间：
2011-08
影响因子：
6
通讯作者：
Bridges, Charles R.
中科院分区：
文献类型：
--
作者：
Fargnoli, Anthony S.;Katz, Michael G.;Yarnall, Charles;Sumaroka, Marina V.;Stedman, Hansell;Rabinowitz, Joseph J.;Koch, Walter J.;Bridges, Charles R.
将基因疗法转化为心力衰竭治疗的两个主要问题是：安全和有效的递送，以及无法建立媒介暴露和体内效应之间的关系。我们提出了单链AAV6-βARKCT循环递送(MCard)的分子心脏手术的药代动力学(PK)分析。利用MCard稳定的心脏特异性传递曲线来确定媒介暴露、半衰期和系统清除量。对5只未成年绵羊进行MCAD1014个基因组拷贝的ScAAV6-βARKCT.在20分钟的再循环间隔时间内采集血样，并用定量聚合酶链式反应(QPCR)进行评估。C(T)曲线被生成并以对数标度表示。生成了用于分析的曝光、半衰期和间隙曲线。采用定量聚合酶链式反应(QPCR)和免疫印迹法(Western Blotting)测定其生物分布。最后，将所有体内转导数据与mCard的PK进行对比，以确定是否存在关联。各时间点的载体浓度分别为：5分钟：9.16±0.15和3.21±0.38；10分钟：8.81±0.19和3.62±0.37；15分钟：8.75±0.12和3.69±0.31；20分钟：8.66±0.22和3.95±0.26；P<；0.00001。载体的半衰期为2.66±0.24分钟。PK模型数据显示，分娩后仅有0.61±0.43%的原始剂量残留在血液中，1周时系统完全清除。PK传递函数显示暴露与体内转导之间呈正相关。βARKCT在所有心脏区域都有表达，而在肝脏中没有表达。MCard可能提供了一种可行的方法来建立媒介暴露和体内转导之间的关系。使用这种方法，有可能解决建立一个有效的治疗窗口的迫切需要。
Two major problems for translating gene therapy for heart failure therapy are: safe and efficient delivery and the inability to establish a relationship between vector exposure and in vivo effects. We present a pharmacokinetics (PK) analysis of molecular cardiac surgery with recirculating delivery (MCARD) of scAAV6-βARKct. MCARD’s stable cardiac specific delivery profile was exploited to determine vector exposure, half-life, and systemic clearance. Five naive sheep underwent MCARD with 1014 genome copies of scAAV6-βARKct. Blood samples were collected over the recirculation interval time of 20 minutes and evaluated with quantitative polymerase chain reaction (qPCR). C(t) curves were generated and expressed on a log scale. The exposure, half-life, and clearance curves were generated for analysis. qPCR and Western blots were used to determine biodistribution. Finally, all in vivo transduction data was plotted against MCARD’s PK to determine if a relationship existed. Vector concentrations at each time point were (cardiac and systemic, respectively): 5 minutes: 9.16 ± 0.15 and 3.21 ± 0.38; 10 minutes: 8.81 ± 0.19 and 3.62 ± 0.37; 15 minutes: 8.75 ± 0.12 and 3.69 ± 0.31; and 20 minutes: 8.66 ± 0.22 and 3.95 ± 0.26; P <.00001. The half life of the vector was 2.66 ± 0.24 minutes. PK model data revealed that only 0.61 ± 0.43% of the original dose remained in the blood after delivery, and complete clearance from the system was achieved at 1 week. A PK transfer function revealed a positive correlation between exposure and in vivo transduction. Robust βARKct expression was found in all cardiac regions with none in the liver. MCARD may offer a viable method to establish a relationship between vector exposure and in vivo transduction. Using this methodology, it may be possible to address a critical need for establishing an effective therapeutic window.
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影响因子：
5
作者：
Katz MG;Swain JD;Tomasulo CE;Sumaroka M;Fargnoli A;Bridges CR
通讯作者：
Bridges CR
影响因子：
6
作者：
Jaski, Brian E.;Jessup, Mariell L.;Mancini, Donna M.;Cappola, Thomas P.;Pauly, Daniel F.;Greenberg, Barry;Borow, Kenneth;Dittrich, Howard;Zsebo, Krisztina M.;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.
DOI：
10.1016/j.jtcvs.2005.07.035
发表时间：
2005-11-01
影响因子：
6
作者：
Bridges, CR;Gopal, K;Stedman, HH
通讯作者：
Stedman, HH
影响因子：
5
作者：
Rengo G;Lymperopoulos A;Leosco D;Koch WJ
通讯作者：
Koch WJ
DOI：
10.1111/j.1752-8062.2010.00190.x
发表时间：
2010-06
期刊：
Clinical and translational science
影响因子：
--
作者：
Zincarelli C;Soltys S;Rengo G;Koch WJ;Rabinowitz JE
通讯作者：
Rabinowitz JE