Biodistribution and safety assessment of AAV2-GAD following intrasubthalamic injection in the rat.
Biodistribution and safety assessment of AAV2-GAD following intrasubthalamic injection in the rat.
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DOI：
10.1002/jgm.1449
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发表时间：
2010-04
影响因子：
3.5
通讯作者：
During, Matthew J.
中科院分区：
文献类型：
--
作者：
Fitzsimons, Helen L.;Riban, Veronique;Bland, Ross J.;Wendelken, Jennifer L.;Sapan, Christine V.;During, Matthew J.
关键词：
将有前途的新生物疗法转化为临床所需的步骤记录得很少。对于基因治疗，在生物分布研究中需要解决一些独特的方面。值得注意的是，载体在预期靶细胞或组织之外的扩散可能导致持续的不必要的生物活性或不可预测的生物事件，因此在开始人体临床试验之前评估与病毒载体介导的基因转移相关的风险至关重要。在这里，我们提出了一个啮齿类动物的研究，包括一个全面的评估载体的生物分布，通过大脑，血液和主要器官的大鼠注射到丘脑底核与重组腺相关病毒（AAV）表达谷氨酸脱羧酶（GAD）。此外，还进行了行为学和组织学分析。在血液或CSF中未检测到AAV基因组，并且在大多数动物中未传播到脑外器官。在脑中，平均97.3%的AAV 2-GAD基因组局限于同侧小脑的区域。AAV 2-GAD对一般健康没有可辨别的影响，并且动物的行为评估没有揭示一般行为、探索、运动或运动对称性的任何改变。除了在啮齿动物和非人灵长类动物中的功效和毒性研究之外，该研究还满足FDA的要求，以支持和补充用于将AAV 2-GAD基因转移至人类脑中以用于帕金森病的潜在治疗的II期临床试验。
The steps necessary to translate promising new biological therapies to the clinic are poorly documented. For gene therapy there are unique aspects that need to be addressed in biodistribution studies. Notably, spread of the vector beyond the intended target cells or tissue may result in persistent unwanted biological activity or unpredictable biological events, thus it is critical to evaluate risks associated with viral vector-mediated gene transfer prior to embarking on human clinical trials. Here we present a rodent study comprising of a comprehensive assessment of vector biodistribution through the brain, blood and major organs of rats injected into the subthalamic nucleus with recombinant adeno-associated virus (AAV) expressing glutamic acid decarboxylase (GAD). In addition, behavioral and histological analyses were also performed. AAV genomes were not detected in blood or CSF, and did not disseminate to organs outside of the brain in the majority of animals. In the brain, an average 97.3% of AAV2-GAD genomes were restricted to the area of the ipsilateral STN. There were no discernable effects of AAV2-GAD on general health and behavioral assessment of the animals did not reveal any alteration in general behavior, exploration, locomotion or motor symmetry. This study met FDA requirements, in addition to efficacy and toxicity studies in rodents and non-human primates, to support and supplement a Phase II clinical trial for gene transfer of AAV2-GAD to the human STN for the potential therapy of Parkinson’s disease.
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影响因子：
5.4
作者：
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通讯作者：
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通讯作者：
During, Matthew J.