Development of Gene Therapy for Enhancing Neurogenesis after Cerebral Infarction

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Gene therapy may show promise for stroke patients, but invasive techniques such as intraventricular or intracerebral injection of therapeutic genes may have limited applicability. The purpose of this study is to develop systemic gene therapy, using macrophages infiltrating the infarct to deliver and express the gene. After permanent middle cerebral artery (MCA) occlusion in rats, an enhanced green fluorecescent protein (EGFP) plasmid conjugate in liposomes was injected via the femoral vein. We also constructed a bicistronic plasmid vector for fibroblast growth factor-2 (FGF-2) as well as EGFP, administering it in other rats with MCA occlusion. EGFP expression in normal brain was absent, but strong in macrophages accumulating along the infarct border. FGF-2 protein production was induced in macrophages along the infarct border after injection of bicistronic FGF-2 and EGFP plasmid vector ; this stimulated proliferation of neural progenitors in the subventricular zone in the ischemic hemisphere compared with control plasmid vectors (61.7±5.2 versus 42.2±5.5 cells per mm^2, n=4 each, P<0.01). In conclusion, systemic gene transfer by liposome to macrophages infiltrating an infarct may prove useful for gene therapy in stroke.