Improved Adeno-associated Viral Gene Transfer to Murine Glioma.
Improved Adeno-associated Viral Gene Transfer to Murine Glioma.
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DOI：
10.4172/2157-7412.1000133
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
I. Zolotukhin;D. Luo;O. Gorbatyuk;Brad E. Hoffman;K. Warrington;R. Herzog;Jeffrey K. Harrison;O. Cao
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文献类型：
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作者：
I. Zolotukhin;D. Luo;O. Gorbatyuk;Brad E. Hoffman;K. Warrington;R. Herzog;Jeffrey K. Harrison;O. Cao
胶质母细胞瘤(GBM)是一种致命的原发脑肿瘤。目前的治疗方法，包括手术切除肿瘤，然后进行化疗和/或放射治疗，并不能显著延长生存期。基底膜的基因疗法正在进行临床试验，例如使用腺病毒载体。虽然腺相关病毒(AAV)代表了另一种载体系统，但有限的对胶质瘤细胞的基因转移阻碍了它的使用。在这里，我们评估了新出现的AAV衣壳基因变种对小鼠脑胶质瘤的基因传递。我们测试了一个不含3个表面暴露酪氨酸残基的突变型AAV2衣壳，AAV2(Y444-500-730F)和一个先前被选为增强神经胶质基因传递的“重排”衣壳(ShH19，包含几个血清型的序列)。AAV2(Y-F)和ShH19在体外对小鼠胶质瘤GL261细胞的转导能力分别是AAV2的2-6倍。在同基因小鼠脑内已建立的肿瘤中，未检测到AAV2基因转移到GL261细胞，但瘤内注射AAV2(Y-F)或ShH19可导致约10%的肿瘤细胞局部转导。此外，还观察到基因转移到肿瘤附近的神经元，而小胶质细胞很少被转导。自我互补载体的使用进一步增加了胶质瘤细胞的转导。总之，这些数据证明了使用最近开发的衣壳变异体改进基于AAV的胶质瘤基因治疗的潜力。
Glioblastoma (GBM) is a deadly primary brain tumor. Current treatment, consisting of surgical removal of the tumor mass followed by chemotherapy and/or radiotherapy, does not significantly prolong survival. Gene therapies for GBM are being developed in clinical trials, for example using adenoviral vectors. While adeno-associated virus (AAV) represents an alternative vector system, limited gene transfer to glioma cells has hampered its use. Here, we evaluated newly emerged variants of AAV capsid for gene delivery to murine glioma. We tested a mutant AAV2 capsid devoid of 3 surface-exposed tyrosine residues, AAV2 (Y444-500-730F), and a "shuffed" capsid (ShH19, containing sequences from several serotypes) that had previously been selected for enhanced glial gene delivery. AAV2 (Y-F) and ShH19 showed improved transduction of murine glioma GL261 cells in vitro by 2- to 6-fold, respectively, over AAV2. While AAV2 gene transfer to GL261 cells in established tumors in brains of syngeneic mice was undetectable, intratumoral injection of AAV2 (Y-F) or ShH19 resulted in local transduction of approximately 10% of tumor cells. In addition, gene transfer to neurons adjacent to the tumor was observed, while microglia were rarely transduced. Use of self-complementary vectors further increased transduction of glioma cells. Together, the data demonstrate the potential for improved AAV-based gene therapy for glioma using recently developed capsid variants.