**5. Gene therapy for the prevention of restenosis**

Gene therapy is the use of genes as a means to achieve high levels of the therapeutic gene product to treat acquired cardiovascular diseases. It can be used as a gene replacement strategy to enhance normal protein function to correct genetic defects. Also, it can be used for local gene transfer to provide a means of delivering a high concentration of therapeutic proteins at the targeted tissue. The vectors used for gene delivery can be classified into two categories, nonviral and recombinant viral vectors. Given the focus of this chapter on gene delivery approaches, we will just briefly discuss the nonviral (polycationic) vector choices. A delivery vehicle of either viral or nonviral origin is essential to carry the foreign gene into a cell. The each of the vector choices has unique advantages and disadvantages.

Viral vectors take advantage of the easy integration of the target gene into the host and longterm expression of gene. Immunogenicity is the major problem of using viral vectors in clinical studies. Attention has turned therefore to nonviral vectors, which possess many advantages over viruses in terms of safety and ease of use, and many clinical studies have now been performed using nonviral technology [7]. Although nonviral vectors are less efficient at introducing and maintaining foreign gene expression compared to viral vectors, they have the profound advantage of being nonpathogenic and nonimmunogenic [8]. Plasmid DNA is the simplest gene delivery vector. In cell transfection, the minimum amount of negatively charged naked plasmid can go by the cell membrane. Therefore, it is necessary to carry genetic materials to target cell by a vector, which are commonly liposomes or polycationic materials.

In nonviral gene therapy, the negatively charged DNA is conjugated with a positively charged cationic polymer. Nevertheless, the conjugate prepared has to be positively charged. By this way, pDNA is wrapped in a protective envelope to be delivered. Once the conjugate is inside the cell, pDNA expresses the targeted proteins to cure the target disease as seen in Figure 2.

**Figure 2.** Polycationic gene transfer.

arterial wall. The medication is entrapped in polymer layers or loaded into polymeric nano‐ particles, and nanoparticles are embedded in polymeric layers. A drug-eluting stent consists

The first part is the metallic scaffold. The metallic scaffold may be constituted by using different types of metallic materials such as stainless steel, nitinol, cobalt, chromium, platinum, gold,

The second part is the drug-eluting polymer-coated inner surface of the scaffold. The polymercoated inner surface of the scaffold is generally used as a drug carrier, which holds and elutes the drug in a controlled manner. The polymers used for DES is generally biodegradable polymers like polylactic acid (PLA), polyglycolic acid (PLGA), and polycaprolactone (PCL). Besides, nonbiodegradable polymers like polybutylmethacrylate (PBMA), polymethylmetha‐ crylate (PMMA), phosphorylcholine, and polyethylene terphthalate (PET) are also evaluated. The third part is the medication that is released from stent directly to arterial wall. Drugs used in DES are immunosuppressive and antiproliferative drugs like sirolimus, everolimus, zotarolimus, paclitaxel, etc., to inhibit neointimal growth, which would cause restenosis [2].

Although the drug-eluting stents significantly reduced the rate of restenosis, it did not completely eliminate restenosis, especially in complex lesions. Additionally, delayed endo‐ thelialization after drug-eluting stent implantation is considered to be the cause of late thrombosis. Therefore, scientists have suggested that gene transfer can be an option to address these problems by inhibiting proliferation of vascular smooth muscle cells (VSMCs) and by promoting endothelialization with some genes [6]. Then scientists used stents as a tool to deliver growth factors, plasmids, and antisense oligonucleotides directly to arterial wall. Several studies have been carried out for the delivery and controlled release of genes encoding antiproliferative proteins, miRNAs, peptide structures, and siRNAs to the target tissues

Gene therapy is the use of genes as a means to achieve high levels of the therapeutic gene product to treat acquired cardiovascular diseases. It can be used as a gene replacement strategy to enhance normal protein function to correct genetic defects. Also, it can be used for local gene transfer to provide a means of delivering a high concentration of therapeutic proteins at the targeted tissue. The vectors used for gene delivery can be classified into two categories, nonviral and recombinant viral vectors. Given the focus of this chapter on gene delivery approaches, we will just briefly discuss the nonviral (polycationic) vector choices. A delivery vehicle of either viral or nonviral origin is essential to carry the foreign gene into a cell. The

Viral vectors take advantage of the easy integration of the target gene into the host and longterm expression of gene. Immunogenicity is the major problem of using viral vectors in clinical studies. Attention has turned therefore to nonviral vectors, which possess many advantages

of three main parts.

418 Muscle Cell and Tissue

magnesium alloy, etc.

through different polymeric materials.

**5. Gene therapy for the prevention of restenosis**

each of the vector choices has unique advantages and disadvantages.

Human gene therapy for the prevention of restenosis is expected to provide important advances in therapeutic restenosis management. If applied in humans, it will be possible to provide long-term beneficial therapeutic effects. However, some key issues, including vector

safety and delivery mechanisms, still have to be resolved before percutaneous gene therapy can be widely applied in clinic. With the aim of inhibition of restenosis, several new types of carriers and technology have been developed, and a great number of gene therapy methods have been studied.

Vascular gene transfer is used to overexpress therapeutically important proteins and correct genetic defects. Promising therapeutic effects have been obtained in animal models of restenosis via transfer of genes, such as encoding vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), nitric-oxide synthase, thymidine kinase, tissue inhibitor of metalloproteinases, etc. [9]. In vascular gene therapy, it is required to combine a therapeutic gene or a therapeutic gene product with an appropriate vector. These complexes are delivered to target cells from a device.
