AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells
AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells
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DOI：
10.1182/blood-2008-07-167510
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发表时间：
2009-09-03
期刊：
影响因子：
20.3
通讯作者：
High, Katherine A.
中科院分区：
文献类型：
--
作者：
Mingozzi, Federico;Meulenberg, Janneke J.;High, Katherine A.
在一项针对脂蛋白脂肪酶 (LPL) 缺乏症的腺相关病毒血清型 1 (AAV-1) 介导的基因转移到肌肉的临床试验中，高剂量组中的 1 名受试者在基因转移后 4 周经历了肌肉酶肌酸磷酸激酶 (CPK) 的短暂增加。同时，在出现与 LPL 表达一致的初始下降趋势后，血浆甘油三酯水平回到基线。我们对参与本研究的受试者的 B 细胞和 T 细胞对载体和转基因产物的反应进行了表征。对经历 CPK 升高的受试者的外周血单核细胞 (PBMC) 进行 IFN-γ 酶联免疫吸附点 (ELISpot) 和细胞内细胞因子染色测定，结果显示衣壳特异性 CD4(+) 和 CD8(+) T 细胞被激活。 8 名受试者中有 4 名对衣壳有可检测到的 T 细胞反应，其外观动力学呈剂量依赖性。对衣壳具有可检测到的 T 细胞反应的受试者也具有较高的抗 AAV-1 IgG3 抗体滴度。没有受试者对 LPL 转基因产物产生 B 或 T 细胞反应。这些发现表明，针对 AAV-1 衣壳的 T 细胞反应具有剂量依赖性。它们是否也限制了转基因在较高剂量下的表达持续时间尚不清楚，并且需要在以后的时间点进行额外的分析。 （血。2009；114：2077-2086）
In a clinical trial for adeno-associated virus serotype 1 (AAV-1)-mediated gene transfer to muscle for lipoprotein lipase (LPL) deficiency, 1 subject from the high-dose cohort experienced a transient increase in the muscle enzyme creatine phosphokinase (CPK) 4 weeks after gene transfer. Simultaneously, after an initial downward trend consistent with expression of LPL, plasma triglyceride levels returned to baseline. We characterized B- and T-cell responses to the vector and the transgene product in the subjects enrolled in this study. IFN-gamma enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining assays performed on peripheral blood mononuclear cells (PBMCs) from the subject who experienced the CPK elevation showed the activation of capsid-specific CD4(+) and CD8(+) T cells. Four of 8 subjects had detectable T-cell responses to capsid with dose-dependent kinetics of appearance. Subjects with detectable T-cell responses to capsid also had higher anti-AAV-1 IgG3 antibody titer. No subject developed B- or T-cell responses to the LPL transgene product. These findings suggest that T-cell responses directed to the AAV-1 capsid are dose-dependent. Whether they also limit the duration of expression of the transgene at higher doses is unclear, and will require additional analyses at later time points. (Blood. 2009; 114: 2077-2086)