Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors
Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors
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DOI：
10.1038/sj.gt.3301541
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发表时间：
2001-09-01
期刊：
影响因子：
5.1
通讯作者：
Sands, MS
中科院分区：
文献类型：
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作者：
Donsante, A;Vogler, C;Sands, MS
使用重组腺相关病毒载体（rAAV）的基因治疗通常被认为是安全的。在一项旨在确定 rAAV 介导的基因治疗对患有溶酶体贮积症、粘多糖贮积症 VII 型 (MPSVII) 的新生小鼠的长期疗效的研究过程中，发现肝细胞癌和血管肉瘤的发病率很高。肝细胞癌首先在 35 周龄的小鼠中被发现，到 72 周龄时，五分之三的 rAAV 治疗的 MPSVII 小鼠出现了类似的病变。以前在使用重组酶或骨髓移植对 MPSVII 小鼠进行的长期研究中从未发现过这些类型的肿瘤。为了确定小鼠品系或 GUSB 表达是否会导致对肿瘤形成的易感性，我们通过组织病理学检查了同一品系的未经治疗的正常小鼠、未经治疗的 MPSVII 小鼠和过表达人 GUSB 的正常小鼠是否存在肿瘤和肝细胞复制增加。这些研究的结果并不表明MPSVII小鼠或过表达人GUSB的小鼠容易形成肿瘤；然而，所检查的动物数量太少，无法得出明确的结论。对肿瘤样本进行的定量 PCR 结果表明，肿瘤可能不是由插入诱变事件和随后转化细胞的克隆扩增引起的。在另一项研究中，注射不同剂量和类型的 rAAV 载体的相对较大的一组小鼠没有出现肝脏或血管肿瘤的证据。尽管肿瘤形成的机制目前尚不清楚，但rAAV载体的致瘤潜力必须在长期体内研究中严格确定。
Gene therapy using recombinant adeno-associated virus vectors (rAAV) is generally considered safe. During the course of a study designed to determine the long-term efficacy of rAAV-mediated gene therapy initiated in newborn mice with the lysosomal storage disease, mucopolysaccharidosis type VII (MPSVII), a significant incidence of hepatocellular carcinomas and angiosarcomas was discovered. A hepatocellular carcinoma was first detected in a 35-week-old mouse and by 72 weeks of age, three out of five rAAV-treated MPSVII mice had similar lesions. These types of tumors had not been seen previously in long-term studies of MPSVII mice using recombinant enzyme or bone marrow transplantation. In an attempt to ascertain whether mouse strain or GUSB expression confers susceptibility to tumor formation, we histopathologically examined untreated normal mice of the same strain, untreated MPSVII mice, and normal mice overexpressing human GUSB for the presence of tumors and increased hepatocyte replication. The results of these studies do not indicate that MPSVII mice or mice overexpressing human GUSB are susceptible to tumor formation; however, the number of animals examined is too small to draw definitive conclusions. Results from quantitative PCR performed on the tumor samples suggest that the tumors are probably not caused by an insertional mutagenesis event followed by the clonal expansion of a transformed cell. In a separate study, a relatively large group of mice injected with varying doses and types of rAAV vectors had no evidence of hepatic or vascular tumors. Although the mechanism of tumor formation is currently unknown, the tumorigenic potential of rAAV vectors must be rigorously determined in long-term in vivo studies.