Published Online
on June 10, 2004

A more recent version of this article appeared on August 1, 2004

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Submitted on January 7, 2004
Revised on March 17, 2004
Accepted on May 5, 2004

Infiltrating Macrophages as In Vivo Targets for Intravenous Gene Delivery in Cerebral Infarction

Shigeru Tanaka MD, PhD; Kazuo Kitagawa MD, PhD^*; Shiro Sugiura MD, PhD; Emi Matsuoka-Omura MD, PhD; Tsutomu Sasaki MD, PhD; Yoshiki Yagita MD, PhD; and Masatsugu Hori MD, PhD

From the Division of Strokology, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: kitagawa{at}medone.med.osaka-u.ac.jp.

Background and Purpose--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).

Conclusion--Systemic gene transfer by liposome to macrophages infiltrating an infarct may prove useful for gene therapy in stroke.

Key words: gene therapy • ischemia • macrophages • growth factors

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