Abstract
Uses of viral vectors have thus far eclipsed uses of non-viral vectors for gene therapy delivery in the clinic. Viral vectors, however, have certain issues involving genome integration, the inability to be delivered repeatedly, and possible host rejection. Fortunately, development of non-viral DNA vectors has progressed steadily, especially in plasmid vector length reduction, now allowing these tools to fill in specifically where viral or other non-viral vectors may not be the best options. In this review, we examine the improvements made to non-viral DNA gene therapy vectors, highlight opportunities for their further development, address therapeutic needs for which their use is the logical choice, and discuss their future expansion into the clinic.
Highlights
Introduction to Gene TherapyGene therapy is the use of nucleic acids to repair, replace, or regulate genes to prevent or treat disease [1]
Mini-intronic plasmid ori : origin of replication; AR: antibiotic resistance; CpG: cytosine-phosphate-guanine dinucleotide; pORT: operator repressor titration plasmids; plasmid with conditional origin of replication (pCOR): plasmids with conditional origin of replication; plasmid free of antibiotic resistance (pFAR): plasmids free of antibiotic resistance; tRNA: transfer RNA; Post-segregational killing (PSK): post-segregational killing; MIDGE: minimalistic immunologically defined gene expression; MiLV: micro-linear vector; PCR: polymerase chain reaction; 1 True of most if not all non-viral DNA vectors; 2 Mini-intronic plasmids are produced as standard plasmids and initially contain the same elements when transfection takes place
Other non-viral vector systems described in this review, such as pFAR and minicircles, have been tested only pre-clinically
Summary
Gene therapy is the use of nucleic acids to repair, replace, or regulate genes to prevent or treat disease [1]. Viral vectors are widely used because of their natural ability to invade cells and deliver a manipulated genetic payload for therapeutic use It is far more difficult for non-viral vectors (RNA or DNA) to transfect many specific cell types, so they are usually complexed with delivery vehicles (e.g., cationic lipids, cationic polymers, etc.) or subjected to forced entry (e.g., electroporation, hydrodynamic injection, etc.). Adenoviral vectors are maintained episomally, which is advantageous [13], but can cause toxicity and immunogenicity [14] Certain viral vectors, such as those based on adenovirus serotype 5 (AdV5) or adeno-associated virus type 2 (AAV2), cannot be used because the virus is so widespread that many people have a pre-existing immunity [15].
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