Infiltrating macrophages as in vivo targets for intravenous gene delivery in cerebral infarction.
OBJECTIVE
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.


METHODS
After permanent middle cerebral artery occlusion in rats, an enhanced green fluorescent 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 middle cerebral artery occlusion.


RESULTS
EGFP expression in normal brain was absent but was 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 mm2, n=4 each, P<0.01).


CONCLUSIONS
Systemic gene transfer by liposome to macrophages infiltrating an infarct may prove useful for gene therapy in stroke.
Tanaka
Shigeru
S
Division of Strokology, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
Kitagawa
Kazuo
K
Sugiura
Shiro
S
Matsuoka-Omura
Emi
E
Sasaki
Tsutomu
T
Yagita
Yoshiki
Y
Hori
Masatsugu
M
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002544:Cerebral Infarction / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D018014:Gene Transfer Techniques; D018773:Genes, erbB-1; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D020244:Infarction, Middle Cerebral Artery; D008081:Liposomes; D008264:Macrophages; D008297:Male; D009474:Neurons / Q000502:physiology; D010957:Plasmids; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000502:physiology
D008081:Liposomes; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins