Nonviral gene therapy is expected to become a regular treatment for a variety of difficult-to-treat diseases, such as cancer and virus infection. Plasmid DNA, which is used in most nonviral gene delivery systems, usually contains, unmethylated cytosine-guanine dinucleotides, so called CpG motifs. CpG motifs are recognized by immune cells as a danger signal, leading to an inflammatory response. Such inflammatory responses could affect the safety and effectiveness of nonviral gene therapy. Therefore, reducing the number of CpG motifs in plasmid DNA has been used to increase the potency of plasmid DNA-based gene therapy. Previous studies have demonstrated that CpG reduction can extend the time period of transgene expression from plasmid DNA after in vivo gene transfer. In this review, the biological functions of the CpG motif are briefly summarized. Then, safety issues of nonviral gene therapy are discussed from the viewpoint of the inflammatory response to the CpG motif in plasmid DNA, and the effects of the CpG motif in plasmid DNA on the transgene expression profile of nonviral gene transfer are reviewed.
"Mini DNA vectors are a promising alternative to conventional plasmids. Because of their smaller size and lack of immunostimulatory bacterial sequences, these vectors show amended biosafety, better biological/immunological compatibility, improved gene transfer, potentially greater bioavailability, and higher cytoplasmic diffusion rates.5,15 "
[Show abstract][Hide abstract] ABSTRACT: Conventional plasmid DNA vectors play a significant role in gene therapy, but they also have considerable limitations: they can elicit adverse immune responses because of bacterial sequences they contain for maintenance and amplification in prokaryotes, their bioavailability is compromised because of their large molecular size, and they may be genotoxic. We constructed an in vivo platform to produce ministring DNA-mini linear covalently closed DNA vectors-that are devoid of unwanted bacterial sequences and encode only the gene(s) of interest and necessary eukaryotic expression elements. Transfection of rapidly and slowly dividing human cells with ministring DNA coding for enhanced green fluorescent protein resulted in significantly improved transfection, bioavailability, and cytoplasmic kinetics compared with parental plasmid precursors and isogenic circular covalently closed DNA counterparts. Ministring DNA that integrated into the genome of human cells caused chromosomal disruption and apoptotic death of possibly oncogenic vector integrants; thus, they may be safer than plasmid and circular DNA vectors.
[Show abstract][Hide abstract] ABSTRACT: Interferon (IFN) gene based therapy has been studied for the treatment of many diseases such as viral infections, cancer and allergic diseases. Non-viral vectors, like plasmid DNA, are promising ways for delivering IFN genes, because of their low immunogenicity and toxicity compared with viral vectors. Potent therapeutic effects of IFN gene transfer will depend on the level and duration of transgene expression after in vivo administration. Therefore, controlling the kinetics of transgene expression of IFNs is a rational approach for improved gene therapy. The design and optimization of plasmid vectors, as well as their route/method of administration, is the key to obtaining high and persistent transgene expression. In this review, we aim to present experimental evidence about the relationships among the properties of plasmid vectors expressing IFNs, the kinetics of transgene expression, and therapeutic effects as well as safety issues.
Journal of Drug Targeting 09/2012; 20(9):764-9. DOI:10.3109/1061186X.2012.716848 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gene transfer is an increasingly utilized approach for research and clinical applications involving the central nervous system (CNS). Vectors for gene transfer can be as simple as an unmodified plasmid, but more commonly involve complex modifications to viruses to make them suitable gene delivery vehicles. This chapter will explain how tools for CNS gene transfer have been derived from naturally occurring viruses. The current capabilities of plasmid, retroviral, adeno-associated virus, adenovirus, and herpes simplex virus vectors for CNS gene delivery will be described. These include both focal and global CNS gene transfer strategies, with short- or long-term gene expression. As is described in this chapter, an important aspect of any vector is the cis-acting regulatory elements incorporated into the vector genome that control when, where, and how the transgene is expressed.
Advances in genetics 10/2014; 87:125-97. DOI:10.1016/B978-0-12-800149-3.00003-2 · 6.76 Impact Factor
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