Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy
Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy
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DOI：
10.1073/pnas.0904514106
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发表时间：
2009-09-22
影响因子：
11.1
通讯作者：
Flotte, Terence R.
中科院分区：
文献类型：
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作者：
Brantly, Mark L.;Chulay, Jeffrey D.;Flotte, Terence R.
α-1抗胰蛋白酶(AAT)缺乏症非常适合作为人类基因转移的靶点。我们进行了一项1期开放标记、剂量递增的临床试验，将表达正常(M)AAT的重组腺相关病毒(RAAV)载体包装成由I.M.递送的1型AAV衣壳。注射。9名AAT缺陷受试者按顺序进入队列，每组3人，剂量分别为6.9×10(12)、2.2×10(13)和6.0×10(13)载体基因组颗粒。4名接受AAT蛋白增强治疗的受试者在载体注射前28天或56天停止治疗。载体给药耐受性良好，仅有轻微的局部反应和1例无关的严重不良事件(细菌性附睾炎)。血液学和临床生化指标均无明显变化。尽管所有受试者在第14天对AAV1衣壳产生了中和抗体和干扰素-γ酶联免疫斑点反应，但在第2和第3组中，所有受试者都表达了上述背景，并在最高剂量水平的队列中保持在正常水平的0.1%至少一年。这些发现表明，对甲型肝炎病毒衣壳的免疫反应是在免疫后发展起来的。在这种情况下，注射表达AAT的血清1型rAAV载体并不能完全消除转导细胞。
Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed a phase 1, open-label, dose-escalation clinical trial of a recombinant adeno-associated virus (rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.m. injection. Nine AAT-deficient subjects were enrolled sequentially in cohorts of 3 each at doses of 6.9 x 10(12), 2.2 x 10(13), and 6.0 x 10(13) vector genome particles per patient. Four subjects receiving AAT protein augmentation discontinued therapy 28 or 56 days before vector administration. Vector administration was well tolerated, with only mild local reactions and 1 unrelated serious adverse event (bacterial epididymitis). There were no changes in hematology or clinical chemistry parameters. M-specific AAT was expressed above background in all subjects in cohorts 2 and 3 and was sustained at levels 0.1% of normal for at least 1 year in the highest dosage level cohort, despite development of neutralizing antibody and IFN-gamma enzyme-linked immunospot responses to AAV1 capsid at day 14 in all subjects. These findings suggest that immune responses to AAV capsid that develop after i.m. injection of a serotype 1 rAAV vector expressing AAT do not completely eliminate transduced cells in this context.