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(Circulation Research. 2000;87:1063.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Gene Therapy for Attenuating Cardiac Allograft Arteriopathy Using Ex Vivo E2F Decoy Transfection by HVJ-AVE–Liposome Method in Mice and Nonhuman Primates

Motohiro Kawauchi¹, Jun-ichi Suzuki¹, Ryuichi Morishita, Yuko Wada, Atsushi Izawa, Naruya Tomita, Jun Amano, Yasufumi Kaneda, Toshio Ogihara, Shinichi Takamoto, Mitsuaki Isobe

From the Department of Cardiovascular Surgery (M.K., S.T.), Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo; Departments of Internal Medicine I (J.S., A.I., M.I.) and Surgery II (Y.W., J.A.), Shinshu University School of Medicine, Matsumoto, Nagano; Department of Cardiovascular Medicine (M.I.), Tokyo Medical and Dental University, Bunkyo-ku, Tokyo; Division of Gene Therapy Science (R.M., Y.K.) and Department of Geriatric Medicine (N.T., T.O.), Faculty of Medicine, Osaka University, Suita, Osaka, Japan.

Correspondence to Jun-ichi Suzuki, Vascular Medicine and Atherosclerosis Unit, Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail jsuzuki{at}rics.bwh.harvard.edu

Abstract—Cardiac allograft arteriopathy, which limits the long-term survival of recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. The transcription factor E2F plays a pivotal role in the coordinated transcription of cell-cycle regulatory genes. To test the hypothesis that double-stranded DNA with specific affinity for E2F (E2F decoy) is effective in preventing intimal hyperplasia, we performed ex vivo single intraluminal delivery of E2F decoy into cardiac allografts of mice and Japanese monkeys using the hemagglutinating virus of Japan (HVJ) artificial viral envelope–liposome method. In murine models, antisense cyclin-dependent kinase 2 (cdk2) kinase oligodeoxynucleotide (ODN) and no transfers were performed to compare the effects. Severe intimal thickening was observed, and multiple cell-cycle regulatory genes were enhanced in untreated allografts. E2F decoy prevented neointimal formation and suppressed these genes for up to 8 weeks, whereas antisense cdk2 kinase ODN had limited effects. In primate models, E2F decoy dramatically prevented neointimal thickening and suppressed multiple cell-cycle regulatory genes, whereas intimal thickening developed in the nontransfected or mismatch decoy-transfected allografts. Gel mobility shift assay proved the specific effects of E2F decoy, and reverse transcriptase–polymerase chain reaction documented that neither complication nor dissemination of HVJ into other organs was observed. We demonstrate that ex vivo gene delivery to allografts is a potent strategy to modify allograft gene expression, resulting in prevention of graft arteriopathy without systemic adverse effects.

Key Words: primate • heart transplantation • transcription factor • arteriosclerosis • gene therapy

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