Long-term pharmacologically regulated expression of erythropoietin in,primates following AAV-mediated gene transfer
Long-term pharmacologically regulated expression of erythropoietin in,primates following AAV-mediated gene transfer
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通过 AAV 介导的基因转移，在灵长类动物体内长期药理调控表达促红细胞生成素
DOI：
10.1182/blood-2004-06-2501
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发表时间：
2005-02-15
期刊：
影响因子：
20.3
通讯作者：
Wilson, JM
中科院分区：
文献类型：
--
作者：
Rivera, VM;Gao, GP;Wilson, JM
基因治疗是一种潜在的递送分泌型治疗性蛋白的途径，但为了获得最佳的安全性和有效性，通常需要对表达进行药理学控制。以前在大型动物模型中实现调控表达的尝试因瞬时表达或对调控蛋白的免疫反应而受挫。在肌肉注射腺相关病毒(AAV)载体给16个灵长类动物后，我们评估了二聚体调控的基因表达系统实现可控的、长期的促红细胞生成素(EPO)生产的能力。静脉或口服二聚体雷帕霉素或免疫抑制活性降低的类似物后，所有动物均表现出剂量反应和完全可逆的EPO和红细胞压积升高。在研究期间，接受优化双载体的动物表现出持续的受调控表达，对EPO或调控蛋白没有明显的免疫反应。同时整合EPO和调控基因的单一载体也得到了类似的结果，包括那些包装成血清1型AAV载体的载体，以允许使用较低的病毒剂量。对于研究时间最长的动物，调控表达已经持续了6年多和26个诱导周期。这些数据表明，一次性或不频繁的基因转移和二聚体调节是一种很有前途的治疗蛋白输送方法。(C)2005年，由美国血液病学会提供。
Gene therapy is a potential route for the delivers of secreted therapeutic proteins, but pharmacologic control of expression will generally be required for optimal safety and efficacy. Previous attempts to achieve regulated expression in large animal models have been thwarted by transient expression or immune responses to regulatory proteins. We evaluated the ability of the dimerizer-regulated gene expression system to achieve controlled, long-term production of erythropoietin (Epo) following intramuscular administration of adeno-associated virus (AAV) vectors to 16 primates. All animals showed dose-responsive and completely reversible elevation of Epo and hematocrit in response to the dimerizer rapamycin, or analogs with reduced immunosuppressive activity, administered intravenously or orally. Animals that received optimized dual vectors showed persistent regulated expression for the duration of the study, with no apparent immune response to Epo or the regulatory proteins. Similar results were obtained with single vectors incorporating both the Epo and regulatory genes, including those packaged into serotype 1 AAV vectors to allow use of lower viral doses. For the longest-studied animal, regulated expression has persisted for more than 6 years and 26 induction cycles. These data indicate that one-time or infrequent gene transfer followed by dimerizer regulation is a promising approach for delivery of therapeutic proteins. (C) 2005 by The American Society of Hematology.