Betz A L, Yang G Y, Davidson B L
Department of Pediatrics, University of Michigan, Ann Arbor 48109-0532, USA.
J Cereb Blood Flow Metab. 1995 Jul;15(4):547-51. doi: 10.1038/jcbfm.1995.68.
Adenoviruses have been proposed as potential vectors for gene therapy in the central nervous system, but there are no reports of their use in the treatment of a brain disease. Because central administration of interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain damage, we determined whether a recombinant adenovirus vector carrying the human IL-1ra cDNA (Ad.RSVIL-1ra) could be used to ameliorate brain injury in permanent focal ischemia. Groups of six rats received intraventricular injections of Ad.RSVIL-1ra or a control adenovirus containing the Escherichia coli beta-galactosidase gene (Ad.RSVlacZ). Histochemical staining for beta-galactosidase 5 days after virus injection indicated that transgene expression was confined primarily to the cells lining the ventricle. The concentrations of IL-1ra injected animals, achieving levels of 9.1 +/- 3.3 ng/g in brain and 23.7 +/- 22.5 ng/ml in CSF. In these animals, cerebral infarct volume resulting from 24 h of permanent middle cerebral artery occlusion was reduced 64%. These studies demonstrate that adenoviral vectors can be used to deliver genes that attenuate brain injury.
腺病毒已被提议作为中枢神经系统基因治疗的潜在载体，但尚无其用于治疗脑部疾病的报道。由于脑室内给予白细胞介素-1受体拮抗剂蛋白（IL-1ra）可减轻缺血性脑损伤，我们确定携带人IL-1ra cDNA的重组腺病毒载体（Ad.RSVIL-1ra）是否可用于改善永久性局灶性缺血中的脑损伤。将六只大鼠分为一组，脑室内注射Ad.RSVIL-1ra或含有大肠杆菌β-半乳糖苷酶基因的对照腺病毒（Ad.RSVlacZ）。病毒注射5天后对β-半乳糖苷酶进行组织化学染色表明，转基因表达主要局限于脑室衬里细胞。注射IL-1ra的动物体内，脑内浓度达到9.1±3.3 ng/g，脑脊液中浓度达到23.7±22.5 ng/ml。在这些动物中，永久性大脑中动脉闭塞24小时导致的脑梗死体积减少了64%。这些研究表明，腺病毒载体可用于递送减轻脑损伤的基因。
