From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.),
Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St
Elizabeth's Medical Center, Tufts University School of Medicine, Boston,
Mass.
Correspondence to Jeffrey M. Isner, MD, St Elizabeth's Medical Center of Boston, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.edu
Background—Preclinical studies have
indicated that angiogenic growth factors can stimulate the development
of collateral arteries, a concept called "therapeutic
angiogenesis." The objectives of this phase 1 clinical trial were (1)
to document the safety and feasibility of intramuscular gene transfer
by use of naked plasmid DNA encoding an endothelial
cell mitogen and (2) to analyze potential therapeutic benefits
in patients with critical limb ischemia.
Methods and Results—Gene transfer was performed in 10 limbs of 9
patients with nonhealing ischemic ulcers (n=7/10) and/or rest
pain (n=10/10) due to peripheral arterial
disease. A total dose of 4000 µg of naked plasmid DNA encoding the
165-amino-acid isoform of human vascular endothelial
growth factor (phVEGF165) was injected directly into the
muscles of the ischemic limb. Gene expression was documented by
a transient increase in serum levels of VEGF monitored by ELISA. The
ankle-brachial index improved significantly (0.33±0.05 to 0.48±0.03,
P=.02); newly visible collateral blood vessels were
directly documented by contrast angiography in 7 limbs; and magnetic
resonance angiography showed qualitative evidence of improved distal
flow in 8 limbs. Ischemic ulcers healed or markedly improved in
4 of 7 limbs, including successful limb salvage in 3 patients
recommended for below-knee amputation. Tissue specimens obtained from
an amputee 10 weeks after gene therapy showed foci of proliferating
endothelial cells by immunohistochemistry. PCR and
Southern blot analyses indicated persistence of small amounts
of plasmid DNA. Complications were limited to transient lower-extremity
edema in 6 patients, consistent with VEGF enhancement of
vascular permeability.
Conclusions—These findings may be cautiously interpreted to
indicate that intramuscular injection of naked plasmid DNA achieves
constitutive overexpression of VEGF sufficient to induce therapeutic
angiogenesis in selected patients with critical limb ischemia.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Constitutive Expression of phVEGF165 After Intramuscular Gene Transfer Promotes Collateral Vessel Development in Patients With Critical Limb Ischemia
Key Words: angiogenesis • genes • ischemia • growth substances
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 S. Babaei, K. Teichert-Kuliszewska, Q. Zhang, N. Jones, D. J. Dumont, and D. J. Stewart Angiogenic Actions of Angiopoietin-1 Require Endothelium-Derived Nitric Oxide Am. J. Pathol., June 1, 2003; 162(6): 1927 - 1936. [Abstract] [Full Text] [PDF]
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F. W. Sellke Gene therapy in cardiac surgery: Is there a role? J. Thorac. Cardiovasc. Surg., May 1, 2003; 125(5): 994 - 997. [Full Text] [PDF]
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 E. Imai Gene Therapy for Renal Diseases: Its Potential and Limitation J. Am. Soc. Nephrol., April 1, 2003; 14(4): 1102 - 1104. [Full Text] [PDF]
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T. D. Henry, B. H. Annex, G. R. McKendall, M. A. Azrin, J. J. Lopez, F. J. Giordano, P.K. Shah, J. T. Willerson, R. L. Benza, D. S. Berman, et al. The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis Circulation, March 18, 2003; 107(10): 1359 - 1365. [Abstract] [Full Text] [PDF]
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N. Tomita, R. Morishita, Y. Taniyama, H. Koike, M. Aoki, H. Shimizu, K. Matsumoto, T. Nakamura, Y. Kaneda, and T. Ogihara Angiogenic Property of Hepatocyte Growth Factor Is Dependent on Upregulation of Essential Transcription Factor for Angiogenesis, ets-1 Circulation, March 18, 2003; 107(10): 1411 - 1417. [Abstract] [Full Text] [PDF]
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E. R Mohler III, S. Rajagopalan, J. W Olin, J. D Trachtenberg, H. Rasmussen, R. Pak, and R. G Crystal Adenoviral-mediated gene transfer of vascular endothelial growth factor in critical limb ischemia: safety results from a phase I trial Vascular Medicine, February 1, 2003; 8(1): 9 - 13. [Abstract] [PDF]
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 H Arakawa, U Ikeda, Y Hojo, S Ueno, M Nonaka-Sarukawa, K Yamamoto, and K Shimada Decreased serum vascular endothelial growth factor concentrations in patients with congestive heart failure Heart, February 1, 2003; 89(2): 207 - 208. [Full Text] [PDF]
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 M. Rajasekaran, A. Kasyan, W. Allilain, and M. Monga Ex Vivo Expression of Angiogenic Growth Factors and Their Receptors in Human Penile Cavernosal Cells J Androl, January 1, 2003; 24(1): 85 - 90. [Abstract] [Full Text] [PDF]
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 J.-S. Silvestre, N. Kamsu-Kom, M. Clergue, M. Duriez, and B. I. Levy Very-Low-Dose Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Induces an Early and Sustained Increase in Neovascularization in Rat Ischemic Legs J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1038 - 1043. [Abstract] [Full Text] [PDF]
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M. Onimaru, Y. Yonemitsu, M. Tanii, K. Nakagawa, I. Masaki, S. Okano, H. Ishibashi, K. Shirasuna, M. Hasegawa, and K. Sueishi Fibroblast Growth Factor-2 Gene Transfer Can Stimulate Hepatocyte Growth Factor Expression Irrespective of Hypoxia-Mediated Downregulation in Ischemic Limbs Circ. Res., November 15, 2002; 91(10): 923 - 930. [Abstract] [Full Text] [PDF]
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 M. R. Jaff Pharmacotherapy for Peripheral Arterial Disease: Emerging Therapeutic Options Angiology, November 1, 2002; 53(6): 627 - 633. [Abstract] [PDF]
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M. C. Cid, J. Hernandez-Rodriguez, M.-J. Esteban, M. Cebrian, Y. S. Gho, C. Font, A. Urbano-Marquez, J. M. Grau, and H. K. Kleinman Tissue and Serum Angiogenic Activity Is Associated With Low Prevalence of Ischemic Complications in Patients With Giant-Cell Arteritis Circulation, September 24, 2002; 106(13): 1664 - 1671. [Abstract] [Full Text] [PDF]
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V. Chekanov, R. Rayel, D. Krum, I. Alwan, J. Hare, T. Bajwa, and M. Akhtare Electrical Stimulation Promotes Angiogenesis in a Rabbit Hind-Limb Ischemia Model Vascular and Endovascular Surgery, September 1, 2002; 36(5): 357 - 366. [Abstract] [PDF]
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 Y. Yang, J.-Y. Min, J. S. Rana, Q. Ke, J. Cai, Y. Chen, J. P. Morgan, and Y.-F. Xiao VEGF enhances functional improvement of postinfarcted hearts by transplantation of ESC-differentiated cells J Appl Physiol, September 1, 2002; 93(3): 1140 - 1151. [Abstract] [Full Text] [PDF]
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T.-S. Li, K. Hamano, K. Suzuki, H. Ito, N. Zempo, and M. Matsuzaki Improved angiogenic potency by implantation of ex vivo hypoxia prestimulated bone marrow cells in rats Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H468 - H473. [Abstract] [Full Text] [PDF]
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S. Pislaru, S. P. Janssens, B. J. Gersh, and R. D. Simari Defining Gene Transfer Before Expecting Gene Therapy: Putting the Horse Before the Cart Circulation, July 30, 2002; 106(5): 631 - 636. [Full Text] [PDF]
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 A. Takahashi, Y. Kureishi, J. Yang, Z. Luo, K. Guo, D. Mukhopadhyay, Y. Ivashchenko, D. Branellec, and K. Walsh Myogenic Akt Signaling Regulates Blood Vessel Recruitment during Myofiber Growth Mol. Cell. Biol., July 1, 2002; 22(13): 4803 - 4814. [Abstract] [Full Text] [PDF]
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B. S. Zuckerbraun and E. Tzeng Vascular Gene Therapy: A Reality of the 21st Century Arch Surg, July 1, 2002; 137(7): 854 - 861. [Abstract] [Full Text] [PDF]
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I. Masaki, Y. Yonemitsu, A. Yamashita, S. Sata, M. Tanii, K. Komori, K. Nakagawa, X. Hou, Y. Nagai, M. Hasegawa, et al. Angiogenic Gene Therapy for Experimental Critical Limb Ischemia: Acceleration of Limb Loss by Overexpression of Vascular Endothelial Growth Factor 165 but not of Fibroblast Growth Factor-2 Circ. Res., May 17, 2002; 90(9): 966 - 973. [Abstract] [Full Text] [PDF]
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S.-i. Yoshimura, R. Morishita, K. Hayashi, J. Kokuzawa, M. Aoki, K. Matsumoto, T. Nakamura, T. Ogihara, N. Sakai, and Y. Kaneda Gene Transfer of Hepatocyte Growth Factor to Subarachnoid Space in Cerebral Hypoperfusion Model Hypertension, May 1, 2002; 39(5): 1028 - 1034. [Abstract] [Full Text] [PDF]
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K. Hamano, T.-S. Li, T. Kobayashi, K. Hirata, M. Yano, M. Kohno, and M. Matsuzaki Therapeutic angiogenesis induced by local autologous bone marrow cell implantation Ann. Thorac. Surg., April 1, 2002; 73(4): 1210 - 1215. [Abstract] [Full Text] [PDF]
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T. T. Rissanen, I. Vajanto, M. O. Hiltunen, J. Rutanen, M. I. Kettunen, M. Niemi, P. Leppanen, M. P. Turunen, J. E. Markkanen, K. Arve, et al. Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 (KDR/Flk-1) in Ischemic Skeletal Muscle and Its Regeneration Am. J. Pathol., April 1, 2002; 160(4): 1393 - 1403. [Abstract] [Full Text] [PDF]
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M. C. Kim, A. Kini, and S. K. Sharma Refractory angina pectoris: Mechanism and therapeutic options J. Am. Coll. Cardiol., March 20, 2002; 39(6): 923 - 934. [Abstract] [Full Text] [PDF]
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M. Shimpo, U. Ikeda, Y. Maeda, M. Takahashi, H. Miyashita, H. Mizukami, M. Urabe, A. Kume, T. Takizawa, M. Shibuya, et al. AAV-mediated VEGF gene transfer into skeletal muscle stimulates angiogenesis and improves blood flow in a rat hindlimb ischemia model Cardiovasc Res, March 1, 2002; 53(4): 993 - 1001. [Abstract] [Full Text] [PDF]
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C. Emanueli, M. Bonaria Salis, T. Stacca, G. Pintus, R. Kirchmair, J. M. Isner, A. Pinna, L. Gaspa, D. Regoli, C. Cayla, et al. Targeting Kinin B1 Receptor for Therapeutic Neovascularization Circulation, January 22, 2002; 105(3): 360 - 366. [Abstract] [Full Text] [PDF]
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 J.A. NAGY, E. VASILE, D. FENG, C. SUNDBERG, L.F. BROWN, E.J. MANSEAU, A.M. DVORAK, and H.F. DVORAK VEGF-A Induces Angiogenesis, Arteriogenesis, Lymphangiogenesis, and Vascular Malformations Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 227 - 238. [Abstract] [PDF]
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K.S. MOULTON Plaque Angiogenesis: Its Functions and Regulation Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 471 - 482. [Abstract] [PDF]
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 R. SCHULZ, C. HUMMEL, S. HEINEMANN, W. SEEGER, and F. GRIMMINGER Serum Levels of Vascular Endothelial Growth Factor Are Elevated in Patients with Obstructive Sleep Apnea and Severe Nighttime Hypoxia Am. J. Respir. Crit. Care Med., January 1, 2002; 165(1): 67 - 70. [Abstract] [Full Text] [PDF]
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 S. B. Freedman and J. M. Isner Therapeutic Angiogenesis for Coronary Artery Disease Ann Intern Med, January 1, 2002; 136(1): 54 - 71. [Abstract] [Full Text] [PDF]
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H. Huwer, C. Welter, C. Ozbek, M. Seifert, U. Straub, P. Greilach, G. Kalweit, and H. Isringhaus Simultaneous surgical revascularization and angiogenic gene therapy in diffuse coronary artery disease Eur. J. Cardiothorac. Surg., December 1, 2001; 20(6): 1128 - 1134. [Abstract] [Full Text] [PDF]
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Y. Taniyama, R. Morishita, K. Hiraoka, M. Aoki, H. Nakagami, K. Yamasaki, K. Matsumoto, T. Nakamura, Y. Kaneda, and T. Ogihara Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene in Rat Diabetic Hind Limb Ischemia Model: Molecular Mechanisms of Delayed Angiogenesis in Diabetes Circulation, November 6, 2001; 104(19): 2344 - 2350. [Abstract] [Full Text] [PDF]
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