Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice
Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice
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DOI：
10.1038/gt.2011.194
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发表时间：
2012-02-01
期刊：
影响因子：
5.1
通讯作者：
Ali, R. R.
中科院分区：
文献类型：
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作者：
Balaggan, K. S.;Duran, Y.;Ali, R. R.
伽玛逆转录病毒载体基因治疗后的插入性突变可引起x连锁严重联合免疫缺陷儿童淋巴细胞增殖的发展。在实验研究中，重组腺相关病毒（rAAV）载体也被报道增加了致癌的易感性。在静止的眼细胞中，载体诱导转化的可能性可能明显低于有丝分裂活跃的细胞，但鉴于rAAV和慢病毒载体在眼部疾病中的临床应用越来越多，对它们在眼睛中的致癌潜力进行具体评估是很重要的。在本研究中，我们研究了rAAV2/2和整合HIV-1载体对p53肿瘤抑制基因敲除（p53(-/-)）小鼠眼内恶性转化高度易感的眼部肿瘤发生率的影响。视网膜下注射高滴度rAAV2/2或整合HIV-1载体在p53（-/-）或p53（+/-）动物中没有诱导肿瘤，也没有显著影响它们的自然寿命。我们的结论是，由这些载体的视网膜下递送引起的任何插入事件似乎不足以引起眼内恶性肿瘤，即使在高度易感的动物中也是如此。这些发现支持了这些载体在眼科应用中的持续发展。基因治疗（2012）19,182-188；doi: 10.1038 / gt.2011.194;2011年11月24日在线发布
Insertional mutagenesis following gene therapy with gammaretroviral vectors can cause the development of lymphoproliferation in children with X-linked severe combined immunodeficiency. In experimental studies, recombinant adeno-associated virus (rAAV) vectors have also been reported to increase susceptibility to carcinogenesis. The possibility of vector-induced transformation in quiescent ocular cells is probably significantly lower than in mitotically active cells, but given the increasing number of clinical applications of rAAV and lentiviral vectors for ocular disease, a specific assessment of their oncogenic potential in the eye is important. In this study, we investigated the effect of rAAV2/2 and integrating HIV-1 vectors upon the incidence of ocular neoplasia in p53 tumour-suppressor gene-knockout (p53(-/-)) mice, which are highly susceptible to intraocular malignant transformation. Subretinal injections of high titre rAAV2/2 or integrating HIV-1 vectors induced no tumours in p53(-/-) or p53(+/-) animals, nor significantly affected their natural longevity. We conclude that any insertional events arising from subretinal delivery of these vectors appear insufficient to cause intraocular malignancy, even in highly susceptible animals. These findings support the continued development of these vectors for ocular applications. Gene Therapy (2012) 19, 182-188; doi:10.1038/gt.2011.194; published online 24 November 2011