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Mol Ther:腺相关病毒载体有促发肿瘤风险

来源:生物谷 2012-10-31 10:33

2012年10月27日 讯 /生物谷BIOON/ --近来,研究人员确定小鼠模型可以帮助评估用于基因治疗的病毒载体的副作用,病毒载体可能会提高肿瘤形成的风险。这项研究发表在Molecular Therapy杂志上。

病毒载体承载病毒将遗传物质传递进入细胞内,如今基因治疗已成为类似胶囊的治疗方式。利用病毒的性质,使用特定的病毒载体以有效地针对某些细胞和细胞核,将遗传物质导入原生基因中。重组腺病毒载体(rAAV),因为它们在人体临床试验中能被安全跟踪记录,因此有利于开展人体临床试验。

事实上,在欧洲获得批准的第一个基因治疗药物就是基于重组腺病毒载体平台,这一基因治疗药物主要治疗一种罕见的疾病。不过,有一些报告指出,一些重组腺病毒载体可能会导致宿主DNA突变。Douglas M. McCarty说:虽然临床前研究已经以压倒性地数量证实重组腺相关病毒治疗的安全性,甚至在许多不同的组织和大型动物模型中都得到了验证,但这项新研究证实了某些腺相关病毒载体而不是一般的腺相关病毒载体可能会促进肝肿瘤的形成。

为了帮助确定哪些载体可能更容易导致有害的突变,以及是什么因素促成了这些变化,McCarty博士研究小组比较了传统设计出的更容易激活细胞基因的腺相关病毒载体。他们测试了病毒载体对一个正常小鼠模型和容易发生肿瘤的小鼠模型的作用。结果表明,经过10个月后,肿瘤易感小鼠观察到多余的肿瘤。McCarty博士说:有了这些肿瘤样本在手,我们可以了解原癌基因是如何被激活的,并可用它来设计出更安全的腺相关病毒载体。(生物谷:Bioon.com)

Patterns of scAAV Vector Insertion Associated With Oncogenic Events in a Mouse Model for Genotoxicity

Lucia E Rosas, Jessica L Grieves, Kimberly Zaraspe, Krista MD La Perle, Haiyan Fu and Douglas M McCarty

Recombinant adeno-associated virus (rAAV) vectors have gained an extensive record of safety and efficacy in animal models of human disease. Infrequent reports of genotoxicity have been limited to specific vectors associated with excess hepatocellular carcinomas (HCC) in mice. In order to understand potential mechanisms of genotoxicity, and identify patterns of insertion that could promote tumor formation, we compared a self-complementary AAV (scAAV) vector designed to promote insertional activation (scAAV-CBA-null) to a conventional scAAV-CMV-GFP vector. HCC-prone C3H/HeJ mice and severe combined immunodeficiency (SCID) mice were infected with vector plus secondary treatments including partial hepatectomy (HPX) and camptothecin (CPT) to determine the effects of cell cycling and DNA damage on tumor incidence. Infection with either vector led to a significant increase in HCC incidence in male C3H/HeJ mice. Partial HPX after infection reduced HCC incidence in the cytomegalovirus-green fluorescent protein (CMV-GFP)–infected mice, but not in the cognate chicken β-actin (CBA)-null infected group. Tumors from CBA-null infected, hepatectomized mice were more likely to contain significant levels of vector DNA than tumors from the corresponding CMV-GFP–infected group. Most CBA-null vector insertions recovered from tumors were associated with known proto-oncogenes or tumor suppressors. Specific patterns of insertion suggested read-through transcription, enhancer effects, and disruption of tumor suppressors as likely mechanisms for genotoxicity.

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