Gene Therapy: Current Treatment Options and Likely Near-Term Developments

Non-Viral Systems

It is against the backdrop of these safety concerns that non-viral vectors have been developed. Non-viral methods have several potential advantages over viral methods including risk free repeat administration (Lam & Dean, 2010), relative ease of large scale production and low host immunogenicity (Al-Dosari & Gao, 2009). Historically low levels of transfection and expression, caused by inability to breach cellular barriers and access the host DNA, have held non-viral vectors back (Atkinson & Chalmers, 2010) and as Lam and Dean (2010) point out; viral vectors have had millennia to evolve efficient methods of infecting hosts with their DNA, non-viral methods have not. The issue is that the gene of interest must get past the membrane of the nucleus and into the host chromatin without being damaged, in order to be expressed; this is now achievable in a number of ways.

Table 2. Some of the major types of viral vector used in gene therapy with DNA incorporation type and summary of main advantages and disadvantages. Data from (Mountain, 2000; Kay et al., 2001; Thomas et al., 2003).

The simplest method of non-viral transfection uses naked DNA and this was first demonstrated in vivo when Wolff et al. (1990) injected protein expression vectors directly into murine models, although the effects of this were fairly long lasting they were only very local. There are a number of other non-viral methods of delivering naked DNA each of which has advantages and disadvantages (Table 3).

Another promising non-viral route involves biochemical vectors. Like other non-viral routes these have low toxicity and low immunogenicity (Al-Dosari & Gao, 2009). The plasmid DNA is packaged in cationic lipids (often cholesterol) which bond well with anionic DNA and also interact with the cell membrane allowing the whole complex access to the cytoplasm where the lipids are absorbed and the plasmid released (Niidome & Huang, 2002). A similar system exists using biocompatible, biodegradable polymers these can be administered intravenously or into airways by aerosol and are used to treat cancer and cystic fibrosis (Al-Dosari & Gao, 2009).

Table 3. Summary of most common direct methods of integrating naked DNA directly into host cells. Data from (Niidome and Huang, 2002; Al-Dosari and Gao, 2009; Lam and Dean, 2010).

The Future of Gene Therapy

The future must involve fewer viral vectors and increased use of direct insertion of naked DNA, or where that is not feasible, the use of biochemical vectors. Nano particles also offer potential as future vectors. Transfection rates will increase as specificity and cell targeting improves. However mutation of diseases, such as cancer and HIV, is likely to mean that the arms race between clinicians and diseases will continue unabated.

Acknowledgements

Thanks to Enrico Ferrari for guidance and comments on an earlier version of this work.

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