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首页> 外文期刊>Neurosurgery >Adenoviral-mediated gene transfer into the canine brain in vivo.
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Adenoviral-mediated gene transfer into the canine brain in vivo.

机译：腺病毒介导的基因在体内转移到犬脑中。

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OBJECTIVE: Glioblastoma multiforme (GBM) is a devastating brain tumor for which there is no cure. Adenoviral-mediated transfer of conditional cytotoxic (herpes simplex virus [HSV] 1-derived thymidine kinase [TK]) and immunostimulatory (Fms-like tyrosine kinase 3 ligand [Flt3L]) transgenes elicited immune-mediated long-term survival in a syngeneic intracranial GBM model in rodents. However, the lack of a large GBM animal model makes it difficult to predict the outcome of therapies in humans. Dogs develop spontaneous GBM that closely resemble the human disease; therefore, they constitute an excellent large animal model. We assayed the transduction efficiency of adenoviral vectors (Ads) encoding beta-galactosidase (betaGal), TK, and Flt3L in J3T dog GBM cells in vitro and in the dog brain in vivo. METHODS: J3T cells were infected with Ads (30 plaque-forming units/cell; 72 h) encoding betaGal (Ad-betaGal), TK (Ad-TK), or Flt3L (Ad-Flt3L). We determined transgene expression by immunocytochemistry, betaGal activity, Flt3L enzyme-linked immunosorbent assay, and TK-induced cell death. Ads were also injected intracranially into the parietal cortex of healthy dogs. We determined cell-type specific transgene expression and immune cell infiltration. RESULTS: Adenoviral-mediated gene transfer of HSV1-TK, Flt3L, and betaGal was detected in dog glioma cells in vitro (45% transduction efficiency) and in the dog brain in vivo (10-mm area transduced surrounding each injection site). T cells and macrophages/activated microglia infiltrated the injection sites. Importantly, no adverse clinical or neuropathological side effects were observed. CONCLUSION: We demonstrate effective adenoviral-mediated gene transfer into the brain of dogs in vivo and support the use of these vectors to develop an efficacy trial for canine GBM as a prelude to human trials.
机译：目的：多形性胶质母细胞瘤（GBM）是一种无法治愈的毁灭性脑肿瘤。腺病毒介导的条件性细胞毒性（单纯疱疹病毒[HSV] 1衍生的胸苷激酶[TK]）​​和免疫刺激性（Fms样酪氨酸激酶3配体[Flt3L]）转基因的转移在同基因颅内引起免疫介导的长期存活。啮齿动物的GBM模型。然而，缺乏大型GBM动物模型使得难以预测人类疗法的结果。狗会发展出与人类疾病极为相似的自发性GBM。因此，它们构成了出色的大型动物模型。我们在体外和在犬脑中检测了编码β-半乳糖苷酶（betaGal），TK和Flt3L的腺病毒载体（Ads）在J3T狗GBM细胞中的转导效率。方法：用编码betaGal（Ad-betaGal），TK（Ad-TK）或Flt3L（Ad-Flt3L）的Ads（30个噬菌斑形成单位/细胞; 72小时）感染J3T细胞。我们通过免疫细胞化学，betaGal活性，Flt3L酶联免疫吸附测定和TK诱导的细胞死亡来确定转基因表达。广告还被颅内注射到健康犬的顶叶皮层中。我们确定了细胞类型特异性转基因表达和免疫细胞浸润。结果：在犬神经胶质瘤细胞中体外检测到了HSV1-TK，Flt3L和betaGal的腺病毒介导的基因转移（45％的转导效率），在体内犬脑中检测到了HSV1-TK，Flt3L和betaGal的基因转移（在每个注射部位周围转导了10 mm区域）。 T细胞和巨噬细胞/活化的小胶质细胞浸润了注射部位。重要的是，未观察到不良的临床或神经病理学副作用。结论：我们证明了在体内腺病毒介导的基因有效地转移到狗的脑中，并支持使用这些载体开发犬GBM的功效试验，作为人类试验的前奏。

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