ABSTRACT
The most efficient gene delivery systems for foreign gene transfer to eukaryotic cells are viruses. In viral vectors, the genetic material is part of the genome of a replicative-defective virus. Penetration, integration, and transcription in the host cell via the viral natural pathway lead to foreign gene expression. Although a variety of viral vectors were developed during the last 25 years [3, 4] and clinical trials using viral vectors have been accomplished [5], their use is hampered by limitations such as the size of the foreign gene to be transferred, the risk of intrinsic viral propagation and immunogenicity [6, 7].Therefore, in order to circumvent the drawbacks associated with viral vectors, a variety of non-viral gene delivery systems have been developed.Synthetic gene delivery systems will be, in principle, devoid of propagation risks, will not induce immune responses, and will not be limited in the size of the foreign gene to be expressed. However, their capacity to transfect cells by a process that includes tissuespecific targeting, cell penetration, transgene integration, and/or transcription remains to be improved. Synthetic gene delivery systems are more a complementary option to virus-mediated gene therapy of human diseases rather than a separate approach. For example, after a first treatment with a viral vector that might palliate but not cure a given disease, an immune response might be induced. The synthetic DNA delivery agent can be useful for a complementary second-round treatment, instead of using a second dose of the viral vector, whose efficacy might be compromised by the immune response switched-on during the first treatment. Synthetic DNA delivery agents are especially recommended for delivering DNA to tissues resistant to viral gene transfer [8]. Moreover, various synergistic systems have been described, exploiting the advantages of both viral and non-viral gene delivery systems, such as adeno-lipofection or retro-lipofection in which infection with adeno virus [9-12] or retrovirus [13-15] is performed in the presence of cationic lipid vectors in tissues, where classical viral transfection is poor, resulting in improved transgene expression. Another synergy between different gene transfer methodologies is exemplified by the plasmovirus [16]. Plasmoviruses are plasmids capable of expressing all the viral genes required for generating infectious particles and packaging a defective genome containing a transgene. Plasmids transfected using cationic lipids transform the transduced cells into packaging cells that release infectious replication-defective
retrovirus vectors (RV) containing a transgene, which will infect nearby neighbor cells. Such a vector can efficiently “propagate” the transgene after transfection with synthetic vectors. This system is especially suited for suicide gene strategies [17]. Finally, the advent of small interfering RNA (siRNA), a class of double-stranded RNA nucleotides composed of 20-25 bases, with a variety of roles in biology, is involved in the RNA interference (RNAi) pathway, where it interferes with the expression of a specific gene [18]. Therefore, siRNA can be used for treating genetic diseases mediated by a pathogenic protein that, once silenced by an appropriate siRNA, can be palliated. An advantage of siRNA is that its low molecular weight allows a better bioavailability as compared to plasmid DNA and its complexion with synthetic gene delivery carriers improves its bio-stability.
