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Advanced Drug Delivery Reviews (v.58, #4)
Current status of polymeric gene delivery systems by Tae Gwan Park; Ji Hoon Jeong; Sung Wan Kim (pp. 467-486).
Gene therapy provides great opportunities for treating diseases from genetic disorders, infections and cancer. To achieve successful gene therapy, development of proper gene delivery systems could be one of the most important factors. Several non-viral gene transfer methods have been developed to overcome the safety problems of their viral counterpart. Polymer-based non-viral gene carriers have been used due to their merits in safety including the avoidance of potential immunogenecity and toxicity, the possibility of repeated administration, and the ease of the establishment of good manufacturing practice (GMP). A wide range of polymeric vectors have been utilized to deliver therapeutic genes in vivo. The modification of polymeric vectors has also shown successful improvements in achieving target-specific delivery and in promoting intracellular gene transfer efficiency. Various systemic and cellular barriers, including serum proteins in blood stream, cell membrane, endosomal compartment and nuclear membrane, were successfully circumvented by designing polymer carriers having a smart molecular structure. This review explores the recent development of polymeric gene carriers and presents the future directions for the application of the polymer-based gene delivery systems in gene therapy.
Keywords: Gene therapy; Non-viral gene delivery; Cationic polymers; Neutral polymers; Tissue engineering
Natural polymers for gene delivery and tissue engineering by Jiyoung M. Dang; Kam W. Leong (pp. 487-499).
Although the field of gene delivery is dominated by viral vectors and synthetic polymeric or lipid gene carriers, natural polymers offer distinct advantages and may help advance the field of non-viral gene therapy. Natural polymers, such as chitosan, have been successful in oral and nasal delivery due to their mucoadhesive properties. Collagen has broad utility as gene activated matrices, capable of delivering large quantities of DNA in a direct, localized manner. Most natural polymers contain reactive sites amenable for ligand conjugation, cross-linking, and other modifications that can render the polymer tailored for a range of clinical applications. Natural polymers also often possess good cytocompatibility, making them popular choices for tissue engineering scaffolding applications. The marriage of gene therapy and tissue engineering exploits the power of genetic cell engineering to provide the biochemical signals to influence proliferation or differentiation of cells. Natural polymers with their ability to serve as gene carriers and tissue engineering scaffolds are poised to play an important role in the field of regenerative medicine. This review highlights the past and present research on various applications of natural polymers as particulate and matrix delivery vehicles for gene delivery.
Keywords: Gene delivery; Gene therapy; Tissue engineering; Natural polymers; Collagen; Alginate; Chitosan; Regenerative medicine
Sustained delivery of plasmid DNA from polymeric scaffolds for tissue engineering by Hannah Storrie; David J. Mooney (pp. 500-514).
The encapsulation of DNA into polymeric depot systems can be used to spatially and temporally control DNA release, leading to a sustained, local delivery of therapeutic factors for tissue regeneration. Prior to encapsulation, DNA may be condensed with cationic polymers to decrease particle size, protect DNA from degradation, promote interaction with cell membranes, and facilitate endosomal release via the proton sponge effect. DNA has been encapsulated with either natural or synthetic polymers to form micro- and nanospheres, porous scaffolds and hydrogels for sustained DNA release and the polymer physical and chemical properties have been shown to influence transfection efficiency. Polymeric depot systems have been applied for bone, skin, and nerve regeneration as well as therapeutic angiogenesis, indicating the broad applicability of these systems for tissue engineering.
Keywords: Cationic polymers; Plasmid DNA condensation; Gene therapy; Tissue engineering; Polymeric scaffolds; Plasmid DNA encapsulation
Viral vectors for gene delivery in tissue engineering by Xiujuan Zhang; W.T. Godbey (pp. 515-534).
The goal of tissue engineering is the production of functional, biocompatible tissues by seeding cells within biological or synthetic scaffolds. One tissue engineering approach involves the genetic modification of cells that are seeded onto (or into) scaffolds prior to implantation. The genetic modification is achieved through gene delivery, with can utilize viral transduction or non-viral transfection systems. Although novel non-viral systems have continued to emerge as innovative vehicles for controlled gene delivery, viruses remain the most efficient means by which exogenous genes can be introduced into and expressed by mammalian cells. Retrovirus, adenovirus, adeno-associated virus and herpes virus are widely studied viral gene transfer systems and have attracted the most attention in the field of transduction. This review thoroughly discusses the genomic structures of each virus type, along with the advantages and disadvantages of their use in tissue engineering applications.
Keywords: Tissue engineering; Gene delivery; Retrovirus; Adenovirus; Adeno-associated virus; Herpes virus; Baculovirus
Tissue engineering by modulated gene delivery by Masaya Yamamoto; Yasuhiko Tabata (pp. 535-554).
Tissue engineering is a newly emerging biomedical form to create a local environment which enables cells to promote the proliferation and differentiation for regeneration induction. The cell-induced regeneration of tissues and organs is achieved by making use of the tissue engineering technology or methodology. Several genetic approaches with virus and non-viral vectors or genetically engineered cells have been attempted to enhance tissue regeneration. The basic idea is to promote the cell proliferation and differentiation as well as the secretion of biological signal molecules for tissue regeneration from cells by gene transfection. For successful gene transfection and expression, it is important to develop drug delivery system (DDS) which allows a therapeutic gene to be delivered specifically to the target cell at an appropriate timing for a certain time period. This paper overviews the recent development of gene-modified tissue engineering, briefly explaining delivery technologies necessary to modulate the efficiency of gene transfection.
Keywords: Drug delivery system; Non-viral gene delivery system; Plasmid DNA; Controlled release; Surgical tissue engineering; Internal tissue engineering
Bone tissue engineering by gene delivery by Michelle D. Kofron; Cato T. Laurencin (pp. 555-576).
Recombinant human bone morphogenetic protein-2 and -7 were recently granted United States Food and Drug Administration approval for select clinical applications in bone repair. While significant progress has been made in the delivery of recombinant osteogenic factor to promote bone healing, the short half-life and instability of the protein requires the delivery of milligram quantities of factor or multiple dosages. The potential of gene therapy for bone regeneration is the delivery of physiological levels of therapeutic protein using natural cellular mechanisms. Experimental investigations have demonstrated this approach uses lower dosages of factor to yield bone healing equivalent to that achieved via the administration of recombinant factor or use of bone grafts. The current states of gene delivery for bone tissue engineering applications and challenges to be met are presented in this review.Over the past couple of years, studies have continued to examine the delivery of the osteogenic factor bone morphogenetic protein using gene therapies. The importance of angiogenesis to bone formation has prompted the development of vascular endothelial growth factor gene expression systems for bone regeneration. Viral vectors, in combination with allograft bone, have been investigated to improve existing surgical care. Newly constructed vectors with reduced immunogenicity and regulated gene expression systems provide a greater degree of control over the timing and level of gene expression. Several advances have allowed bone tissue engineering by gene delivery to advance beyond serving as a potential treatment for isolated bone defects and fractures to a gene therapy approach for the treatment of genetic based bone diseases, such as osteogenesis imperfecta.
Keywords: Gene therapy; Bone tissue engineering; Growth factors; Transcription factors; Bone morphogenetic protein; Viral vectors; Non-viral vectors; Osteoporosis; Osteogenesis imperfecta; Bone regeneration
The role of gene therapy for craniofacial and dental tissue engineering by Brian Nussenbaum; Paul H. Krebsbach (pp. 577-591).
Basic science advances in bone tissue engineering using osteoinductive protein therapy have already been translated to the use in patients with selected orthopedic problems. The story of the development of bone morphogenetic protein (BMP) osteoinductive therapy, from the discovery of this class of molecules in 1965 to the publication of randomized clinical trials in 2001 for tibial non-unions and 2002 for spinal fusion, is truly fascinating. Both clinical studies showed healing equivalence of the BMP-bioimplant compared to a free non-vascularized bone graft but without the associated donor site morbidity. These advances unfortunately have not lead to rapid application of using BMP osteoinductive protein therapy for reconstructing most craniofacial bone defects, with clinical case series beginning to be reported only for limited small-sized defects. This is a reflection of the complexity and unique characteristics of most craniofacial defects, which will likely require a more robust osteoinductive signal than delivering recombinant protein on a scaffold for clinically meaningful bone regeneration. Gene therapy approaches are promising for overcoming the unique challenges that are characteristic of craniofacial and dental defects.
Keywords: Craniofacial; Tissue engineering; Gene therapy; Bone morphogenetic protein
Gene delivery strategies for cartilage tissue engineering by Anita Saraf; Antonios G. Mikos (pp. 592-603).
Tissue engineering is a multifaceted technology developed with a purpose of regenerating complex tissues and organs. Cartilage regeneration continues to challenge engineers and a new wave of efforts focus on developing strategies that provide sustained stimulation to cells by growth factors and other biological molecules to promote their differentiation into chondrocytes. Though significant research is dedicated to developing controlled release systems that deliver growth factors directly, a simpler approach to resolving this dilemma involves converting cells into protein producing factories. This is done through gene delivery. Gene Therapy studies published for articular diseases such as rheumatoid and osteoarthritis provide valuable information regarding different types of cells, gene delivery vectors and genes that can potentially be used to regenerate cartilage. Tissue engineering approaches provide the opportunity to combine two or more strategies used for Gene Therapy thus far and create a cohesive system that addresses both cartilage degeneration and synthesis simultaneously. Adopting gene transfer techniques for tissue engineering is a relatively novel approach, as non-viral gene delivery vectors are continually optimized for therapeutic purposes, and reservations about viral vectors have increasingly dampened their appeal. However, every element involved in gene transfection (i.e., the cell, vector and gene) is a variable which decides the physiological and biomechanical properties of the cartilage produced, and significant work still needs to be done in understanding the contribution of each of these factors to cartilage regeneration.
Keywords: Abbreviations; BMP-2; Bone Morphogenic Protein 2; BMP-7; Bone Morphogenic Protein 7; CDC; Center for Disease Control and Prevention; cDNA; complementary Deoxyribonucleic Acid; ECM; Extracellular Matrix; GFP; Green Fluorescent Protein; IGF-1; Insulin-like Growth Factor 1; IL-4; Interleukin 4; IL-1RA; Interleukin 1 Receptor Antagonist; IL-10; Interleukin 10; IL-13; Interleukin 13; MMP; Matrix Metalloproteinase; MSC; Mesenchymal Stem Cell/ Marrow Stromal Cell; PGA; Poly(glycolic acid); SMADs; Smooth Muscle Actin (SMA) and Mitotic spindle Assembly checkpoint (MAD) proteins; TGF-β; Transforming Growth Factor β; TGF-β1; Transforming Growth Factor β1; TGF-β2; Transforming Growth Factor β2; TGF-β3; Transforming Growth Factor β3; TIMP; Tissue Inhibitors of Matrix Metalloproteinase; TIMP-1; Tissue Inhibitor of Matrix Metalloproteinase 1; TIMP-3; Tissue Inhibitor of Matrix Metalloproteinase 3; TNF-α; Tumor Necrosis Factor αCartilage tissue engineering; Genes; Gene delivery; Gene Therapy; Gene delivery vectors; MSCs; Chondrocytes; Synovial cells
Cardiovascular gene delivery: The good road is awaiting by L.P. Brewster; E.M. Brey; H.P. Greisler (pp. 604-629).
Atherosclerotic cardiovascular disease is a leading cause of death worldwide. Despite recent improvements in medical, operative, and endovascular treatments, the number of interventions performed annually continues to increase. Unfortunately, the durability of these interventions is limited acutely by thrombotic complications and later by myointimal hyperplasia followed by progression of atherosclerotic disease over time. Despite improving medical management of patients with atherosclerotic disease, these complications appear to be persisting. Cardiovascular gene therapy has the potential to make significant clinical inroads to limit these complications. This article will review the technical aspects of cardiovascular gene therapy; its application for promoting a functional endothelium, smooth muscle cell growth inhibition, therapeutic angiogenesis, tissue engineered vascular conduits, and discuss the current status of various applicable clinical trials.
Keywords: Thrombosis; Myointimal hyperplasia (IH); Gene delivery; Endothelialization; Endothelial cell (EC); Vascular smooth muscle cell (SMC); Extracellular matrix (ECM)