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(Circulation. 1996;94:3065-3066.)
© 1996 American Heart Association, Inc.
Articles |
Angiogenic Gene Therapy
A Leg to Stand On?
the Cardiovascular Division, Hospital of the University of Pennsylvania (Philadelphia).
Key Words: Editorials • genes • cardiovascular disease
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Introduction |
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Gene therapy for cardiovascular disease offers some of the greatest opportunities and challenges in the growing field of molecular medicine. The challenges in this field fall into three broad categories. The first relates to our state of knowledge regarding the biology of the diseases we wish to target, which must be sufficiently advanced to identify appropriate genes as targets for manipulation. The second relates to the development of biological vector systems that are suitable for genetic modification of the cardiovascular system, combining efficiency of gene transfer, ease of preparation, and acceptable side effect profile. The third relates to gene vector delivery technologies, which must be tailored to the particular requirements of the cardiovascular system and the disease to be treated. The report by Tsurumi and colleagues1 in this issue of Circulation takes advantage of recent progress in all three areas to demonstrate that although gene therapy for selected cardiovascular syndromes is not yet a clinical reality, it may no longer be only a distant speck on the therapeutic horizon.
Peripheral vascular disease, predominantly affecting the lower extremities, has a relatively low mortality but results in considerable morbidity and disability. Both angioplasty and reconstructive surgery are effective treatment options for many patients with peripheral arterial insufficiency, restoring adequate perfusion and resulting in the alleviation of disabling symptoms. However, these procedures are associated with considerable risks, notably restenosis after peripheral angioplasty and cardiac complications of vascular surgery. In addition, the severity and progressive nature of this disease often limit these treatment options, resulting in persistent, disabling symptoms or limb loss. Peripheral vascular disease represents an attractive target for a gene therapy approach to restoration of effective limb perfusion in selected patients. Tsurumi and colleagues have taken an important step toward making gene therapy for peripheral vascular disease a clinical reality. In addition to presenting what may represent an effective gene therapy strategy for treating peripheral artery insufficiency, the authors describe what many in the field consider the real target: development of such strategies for treating coronary artery insufficiency. The choice of making peripheral arterial disease an initial target is a rational one because complications from interventions in the peripheral circulation are less likely to be life threatening. The present study illustrates nicely both the tantalizing potential and the frustrating reality of developing such a therapeutic approach.
Dr Jeffrey Isner and his colleagues1 have taken a novel approach to the problem of peripheral artery insufficiency with encouraging results. This group has been at the forefront of angiogenic gene therapy for peripheral artery insufficiency, publishing several studies over the past few years that provide the background for the present work.2 3 4 The choice of vascular endothelial cell growth factor (VEGF) makes good biological sense for several reasons. After the cloning and characterization of VEGF in 1989,5 our knowledge of its biology and therapeutic potential has grown rapidly. VEGF is an endothelial cell–specific cytokine by virtue of the fact that expression of VEGF receptors is restricted to this cell type. Investigators have shown that, in addition to promoting new vessel formation in areas of normal perfusion, the expression of both the cytokine and its receptors is enhanced by tissue ischemia, thus rendering ischemic areas more responsive to even low concentrations of VEGF. Its activity leads to new vessel formation when administered as either the recombinant protein or as DNA encoding the gene as part of an expression vector, satisfying the requirement of demonstrating biological relevance to the clinical problem under study. As the authors point out, the recombinant protein has not been developed as a therapeutic agent beyond the research setting. The approach of delivering a vector containing DNA encoding VEGF to targeted cells of the host resembles gene therapy strategies being developed for many other clinical problems and therefore shares the requirement of demonstrating efficient gene transfer.
Although plasmid DNA is one of the least efficient gene transfer systems currently in use, it is comparatively simple to prepare and relatively free of serious side effects when administered. The present study takes advantage of a peculiarity of plasmid DNA–mediated gene transfer. When applied to most cells and tissues, plasmid DNA–mediated gene transfer is a low efficiency process and is considered too inefficient to be of significant clinical benefit in most applications. Gene transfer to skeletal muscle stands out as a notable exception since Wolff and colleagues showed that plasmid DNA–mediated gene transfer to skeletal muscle is an efficient means of expressing engineered genes in vivo. Others have shown that physiologically meaningful amounts of recombinant protein can be secreted by skeletal muscle that has been genetically modified by adenoviral vectors in situ7 or containing implanted myoblasts that have been modified ex vivo.8 9 10 11 The limited persistence of plasmid DNA–mediated gene transfer to skeletal muscle and the undefined clearance mechanisms responsible for it remain an important challenge to the clinical usefulness of this approach. These issues notwithstanding, the present report represents a clever application of this approach to the problem of peripheral arterial insufficiency.
Isner and colleagues have previously shown that vascular delivery of plasmid DNA encoding VEGF can promote the development of additional collaterals after surgical devascularization of the rabbit hindlimb. As the authors point out, an important difference between humans with peripheral vascular disease and the animal model is the often diffuse nature of the human disease, making vascular access difficult in the region most in need of therapy. The present study combines the biological rationale of VEGF-promoted angiogenesis with the previously demonstrated efficacy of plasmid DNA–mediated gene transfer to skeletal muscle to achieve local delivery of physiologically apparent expression of VEGF in an area in need of therapy, the ischemic muscle of the surgically devitalized rabbit hindlimb. The data presented demonstrate the augmentation of collateral formation in the VEGF gene–treated limb and include a series of physiological measurements further supporting the angiographic and histological results. Thus, this study satisfies another requirement of an effective gene therapy strategy using a simple and effective delivery technology.
Despite these notable results, caution must be exercised before extending this approach to routine clinical application. Although the presence of regional ischemia enhances the responsiveness to VEGF, there is a significant degree of "autocollateralization" due to native mechanisms alone, providing "noise" against which the "signal" must be measured. For example, when assessed by the blood pressure ratio of the affected to the unaffected limb, the ratio in the gene treated group increases 
2.3-fold compared with baseline measurements performed after induction of ischemia but before gene transfer. The same measurement in the sham-treated animals increased 2-fold. Thus, the signal of enhanced blood pressure in the VEGF-treated animals must be compared with the noise of the nearly comparable improvement in the sham-treated animals. Perhaps the more important limitation of this model is the subacute nature of the lesion, which although a necessity of the experimental preparation, may not faithfully mimic the human disease, which is the ultimate target of these experiments. The diffuse and chronic nature of the human disease, which the authors mention as posing difficulties in delivering VEGF gene therapy via the circulation, may also reduce the predictive value of the model for the clinical success of the intramuscular approach. This difference between the animal model and the human disease may be critical, as the brief duration of gene expression demonstrated in this report might be insufficient to create meaningful collaterals in the more diffuse and chronic setting of the human disease. Finally, the ultimate question that this study provokes but does not yet address is whether angiogenic therapy, regardless of type of vector or route of delivery, can stimulate a sufficient increase in perfusion to bring about healing of ischemic tissue lesions or lasting relief from painful symptoms. This remains the challenge of angiogenic therapy for peripheral artery disease and of gene therapy for cardiovascular disease in general.
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Footnotes |
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The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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Tsurumi Y, Takeshita S, Chen D, Kearney M, Rossow ST, Passeri J, Horowitz JR, Symes JF, Isner JM. Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation.. 1996;94:3281-3290.
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Takeshita S, Pu LQ, Stein LA, Sniderman AD, Bunting S, Ferrara N, Isner JM, Symes JF. Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia. Circulation. 1994;90(suppl II):228-234.
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Takeshita S, Zheng LP, Asahara T, Reissen R, Brogi E, Ferrara N, Symes JF, Isner JM. In vivo evidence of enhanced angiogenesis following direct arterial transfer of the plasmid encoding vascular endothelial growth factor. Circulation. 1993;88(suppl I):I-476. Abstract.
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Takeshita S, Zheng LP, Brogi E, Kearney M, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM. Therapeutic angiogenesis: a single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest.. 1994;93:662-670.
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Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science.. 1989;246:1306-1309.
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Wolff JA, Ludtke JJ, Acsadi G, Williams P, Jani A. Long-term persistence of plasmid DNA and foreign gene expression in mouse muscle. Hum Mol Genet.. 1992;1:363-369.
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Tripathy SK, Goldwasser E, Lu MM, Barr E, Leiden JM. Stable delivery of physiologic levels of recombinant erythropoietin to the systemic circulation by intramuscular injection of replication-defective adenovirus. Proc Natl Acad Sci U S A.. 1994;91:11557-11561.
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Barr E, Leiden JM. Systemic delivery of recombinant proteins by genetically modified myoblasts. Science.. 1991;254:1507-1509.
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Dai Y, Roman M, Naviaux RK, Verma IM. Gene therapy via primary myoblasts: long-term expression of factor IX protein following transplantation in vivo. Proc Natl Acad Sci U S A.. 1992;89:10892-10895.
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Dhawan J, Pan LC, Pavlath GK, Travis MA, Lanctot AM, Blau HM. Systemic delivery of human growth hormone by injection of genetically engineered myoblasts. Science.. 1991;254:1509-1512.
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Yao S-N, Smith KJ, Kurachi K. Primary myoblast-mediated gene transfer: persistent expression of human factor IX in mice. Gene Ther.. 1994;1:99-107.[Medline]
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