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Gene therapy to prevent restenosis, the Boston experience
Abstract
The delivery of genetic material to the vessel wall is being explored as a means to treat disorders of the vasculature. Gene therapy offers the possibility to directly or indirectly influence the molecular pathways that are disregulated. With regard to postangioplasty restenosis, gene therapy is most often aimed at inhibition of vascular smooth muscle cell (VSMC) proliferation. Here, we review the results of studies in our laboratories that have investigated a number of different strategies to inhibit proliferative vessel wall lesions. These strategies include the administration of genes that block cell cycle progression, induce apoptosis, or promote the growth of vascular endothelium.
... Gene therapy is under investigation for various kinds of cardiovascular diseases [Meyerson, 1999, Morishita et al., 2001,Kozarsky, 2001,McKay, 2001,Nikol, 2001,Isner, 2002, using many different therapeutic genes [Tio et al., 1998,Nakamura, 2002. For several prevalent disease conditions, e.g. ...
Numerous gene therapy vectors, both viral and non-viral, are taken into the cell by endocytosis, and for efficient gene delivery the therapeutic genes carried by such vectors have to escape from endocytic vesicles so that the genes can further be translocated to the nucleus. Since endosomal escape is often an inefficient process, release of the transgene from endosomes represents one of the most important barriers for gene transfer by many such vectors. To improve endosomal escape we have developed a new technology, named photochemical internalisation (PCI). In this technology photochemical reactions are initiated by photosensitising compounds localised in endocytic vesicles, inducing rupture of these vesicles upon light exposure. The technology constitutes an efficient light-inducible gene transfer method in vitro, where light-induced increases in transfection or viral transduction of more than 100 and 30 times can be observed, respectively. The method can potentially be developed into a site-specific method for gene delivery in vivo. This article will review the background for the PCI technology, and several aspects of PCI induced gene delivery with synthetic and viral vectors will be discussed. Among these are: (i) The efficiency of the technology with different gene therapy vectors; (ii) use of PCI with targeted vectors; (iii) the timing of DNA delivery relative to the photochemical treatment. The prospects of using the technology for site-specific gene delivery in vivo will be thoroughly discussed, with special emphasis on the possibilities for clinical use. In this context our in vivo experience with the PCI technology as well as the clinical experience with photodynamic therapy will be treated, as this is highly relevant for the clinical use of PCI-mediated gene delivery. The use of photochemical treatments as a tool for understanding the more general mechanisms of transfection will also be discussed.
Recent technological advances in gene transfer in addition to a precise understanding of the molecular basis of many diseases have provided the tools necessary for a new approach to the treatment of both inherited and acquired diseases. This approach, called gene therapy, has the potential of providing long-term and cost effective treatment for some inherited diseases which have few other therapeutic options as well as enabling novel methods for the delivery of therapeutic proteins for the treatment of many acquired diseases. We and others are exploring the potential application of this technology in tissue repair. One primary focus has been to transfer genes encoding wound healing growth factors, a broad class of proteins which control local events in tissue repair such as cell proliferation, migration and the formation of extracellular matrix. Using several different strategies for gene transfer, wound healing growth factor genes have been successfully introduced and expressed in cells and tissues in vitro as well as in vivo. Various experimental models of wound healing and tissue repair have been used to evaluate the efficacy of this new and exciting approach to tissue repair and regeneration.
The morbidity and mortality from chronic wounds of varying etiology present a significant health care problem. Multiple local disturbances and systemic disease can impair wound healing. Recently, experiments with tissue cultures and animal models have revolutionized the understanding of wound healing and the pathophysiological processes involved. In cooperation with clinicians and industrial partners novel therapeutic concepts including the topical application of growth factors and cell therapies have been developed. Cytokines that have been tested in clinical studies include epidermal growth factor, platelet-derived growth factor and fibroblast growth factor. These studies showed that an important aspect of the growth factor wound healing paradigm is the effective delivery of these polypeptides to the wound site. Current drug delivery strategies suffer from the inherent loss of drug activity due to the combined effects of physical inhibition and biological degradation. A molecular genetic approach in which genetically modified cells synthesize and deliver the desired growth factor in a time-regulated manner is a powerful means to overcome the limitations associated with the topical application of recombinant growth factor proteins.
Adenovirus (Ad) infections in immunocompromised hosts have increased in frequency as the number of patients with transplants of bone marrow, liver, kidney, heart and other organs increase in number and survive longer. The numbers of such patients have also increased because of the emergence of the HIV epidemic. Ad infections with the 51 different serotypes recognised to date have few pathognomonic signs and symptoms, and thus require a variety of laboratory-based procedures to confirm infection. These viruses have the ability to target various organs with relative serotype specificity and can cause diverse manifestations including serious life-threatening diseases characteristic of the organs involved. Ads have cytolytic and immunoregulatory properties. The clinical dilemma remains the prompt recognition of Ad-related disease, the differentiation of Ad infection from Ad disease and the differentiation from other causative agents. Since the armamentarium of effective antiviral agents available to treat Ads is unproven by controlled trials and the virus is often not acquired de novo, it is difficult to prevent reactivation in immunodeficient hosts or new acquisition from donor organs. Timely discontinuation of immunosuppressive agents is necessary to prevent morbid outcomes. The clinical diseases, diagnostic tests, antiviral agents and biological aspects of the Ads as pathogens in immunocompromised patients are discussed in the context of this review. Some of the newer diagnostic tests are based on the well-studied molecular biology of Ads, which also have been attenuated by selective viral DNA deletions for use as vectors in numerous gene therapy trials in humans.
Disruption of a high risk plaque is known as the primary cause of cardiovascular events. Characterization of arterial wall components has become an essential adjunct in the identification of patients with plaques prone to rupture. Magnetic Resonance Imaging (MRI) has been revealed as one of the noninvasive tools possibly capable of identifying and characterizing high risk atherosclerotic plaque. MRI may facilitate diagnosis, and guide and serially monitor interventional and pharmacological treatment of atherosclerotic disease. In addition, it permits the simultaneous assessment of the anatomy, morphology, and hemodynamics for the study of flow-induced atherogenesis. It possibly will identify asymptomatic patients with subclinical atherosclerosis. This has potential significance for the improvement of strategies in primary and secondary prevention.
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