PerspectiveNon-viral is superior to viral gene delivery
Section snippets
Use of non-viral vector in clinical trials is increasing
The success of gene therapy is highly dependent on the delivery vector, which can be generally categorized into viral and non-viral vector. Viral vector has dominated the clinical trials in gene therapy for its relatively high delivery efficiency. However, after the adverse events in clinical trials (i.e., adenovirus vector caused patient death in 1999 and retrovirus vector induced a lymphoproliferative disorder in 2002–2003), the safety issue of the gene vector became a major concern that has
Non-viral delivery is effective: hydrodynamic injection of naked DNA transfected 30–40% hepatocytes
Hydrodynamic delivery involves injection of a large volume of DNA solution for a mouse (8–9% of the body weight) in approximately 5 s via the tail vein [3], [4]. The rapid and large volume injection of DNA solution exceeds the cardiac output and causes a transient overflow in the inferior vena cava, which induces DNA solution to flow into the liver. This is followed by a rapid rise of intra-hepatic pressure, liver expansion and reversible disruption of the liver fenestrae. DNA is thus delivered
Non-viral vector is very specific: formulation and targeting ligand technologies enable non-viral vector to be tissue specific
Immunoliposome (antibody-modified liposome) was first reported by our laboratory in 1981 for cell-specific delivery [6]. This approach involves surface modification of delivery carriers with a targeting ligand (antibody, protein, peptide or small molecule compound) and has been widely used in the drug delivery field. Chang's group developed the nano-immunoliposome complex to deliver siRNA and found that siRNA was specifically accumulated in the primary and metastatic tumor, while other normal
Non-viral vector can be long lasting in gene expression: minicircle DNA and co-administration of site-specific integration plasmid showed long-term gene expression
Mark Kay's group found that covalent linkage of bacterial DNA to the expression cassette substantially silenced the transgene in vivo. Therefore, they constructed a DNA vector that intra-molecularly recombined into a minicircle vector without the bacterial backbone [11], [12]. Minicircle DNA vector transfected with a non-viral carrier showed improved in vivo transgene expression and persistent expression. Groth and colleagues have demonstrated that co-administration of a bacteriophage ΦC31
Non-viral vector is safe: inflammatory toxicity of non-viral vector can be managed by eliminating CpG motifs in the plasmid, decreasing the interaction of vector and immune cells and using immunosuppressive agents
Systemic injection of lipoplex, the most commonly used non-viral vector, induces high levels of pro-inflammatory cytokines, leading to systemic toxicity and reduced duration of gene expression. Kupffer cells, the macrophages in the liver, are responsible for uptake of the lipoplex and the production of pro-inflammatory cytokines. Moreover, CpG motifs in the plasmid are agonists for the endosomal toll-like receptor 9, which induces a large spectrum of the immune response. Strategies to reduce
Conclusion: non-viral vector is superior to viral vector
Viral vectors are generally more efficient than non-viral vectors if one calculates the transfection efficiency per gene delivered. However, vectors are not only judged by their efficiency but also safety, which is actually more important according to current US FDA clinical trial regulations. Safe delivery includes the use of low immunogenic components for the vector and specific delivery to the diseased tissue, with which viral vector is struggling to achieve. Non-viral vector is superior to
Future directions and perspectives
Full understanding of gene delivery barriers helps rational design of a more efficient delivery carrier [16]. Therefore, intensive mechanistic studies need to be performed to have more insightful information of the barriers that prevent effective transfection of non-viral vector. We expect to see an increased number of novel materials for overcoming the barriers synthesized and incorporated in the delivery formulation. Pharmacokinetic studies of the vector allowing the prediction of efficacy
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