Adenoviral Vector

Adenovirus is a double stranded DNA virus with an approximately 36-kb genome. First generation adenoviral vectors are created by replacing the viral E1 gene with a reporter or a therapeutic gene expression cassette. The maximal packaging capacity of the first generation adenoviral vector is 8 kb. The biggest problem with adenoviral vectors is the host immune response. In general, transgene expression reaches the peak within one week and then rapidly reduces to the preinfection levels in 2-4 weeks. In an effort to reduce immune response and also to further increase the packaging capacity, gutted adenoviral vectors were developed (Chen et al. 1997; Clemens et al. 1996; Kochanek et al. 1996; Mitani et al. 1995; Morsy et al. 1998; Parks et al. 1996; Schiedner et al. 1998). The only viral elements in gutted adenovirus are the viral ITR and the packaging signal. All viral genes are deleted.

Several laboratories have explored gutted adenovirus for muscle gene therapy, in particular, for delivering the full-length dystrophin coding sequence to mdx mice (Bilbao et al. 2005; Clemens et al. 1996; DelloRusso et al. 2002; Dudley et al. 2004; Gilbert et al. 2002, 2003 ; Haecker et al. 1996; Jiang et al. 2004a, b; Kochanek et al. 1996; Matecki et al. 2004; Reay et al. 2008). Collectively, these studies reveal full-length dystrophin expression, reduced host immune response, amelioration of muscle pathology and enhanced muscle contractility. However, because of immune elimination, long-term expression remains a challenge.

Fig. 12.3 (continued) The bar graph shows the relative transduction efficiency of the dual vectors compared to that of the single intact LacZ vector. Data are mean ± standard error of mean, N = 4. O, overlapping vectors; T, trans-splicing vectors; H, hybrid vectors. Asterisk, the relative b-gal activities in trans-splicing or hybrid vector infected muscles were significantly higher than that in overlapping vector infected muscles. Cross, the relative b-gal activity in hybrid vector infected muscles is significantly higher than that in trans-splicing vector infected muscles

Fig. 12.3 (continued) The bar graph shows the relative transduction efficiency of the dual vectors compared to that of the single intact LacZ vector. Data are mean ± standard error of mean, N = 4. O, overlapping vectors; T, trans-splicing vectors; H, hybrid vectors. Asterisk, the relative b-gal activities in trans-splicing or hybrid vector infected muscles were significantly higher than that in overlapping vector infected muscles. Cross, the relative b-gal activity in hybrid vector infected muscles is significantly higher than that in trans-splicing vector infected muscles

To further limit the cellular immune reaction, several novel strategies have been explored. These include the use of the utrophin gene (an endogenous homologue of dystrophin), species-specific dystrophin gene, muscle-specific promoter, immune-modulating strategies and neonatal or in utero gene delivery (Bilbao et al. 2005; DelloRusso et al. 2002; Deol et al. 2007; Jiang et al., 2004a, b; Reay et al. 2008). Together, these approaches have significantly extended transgene expression from the gutted adenovirus. Admittedly, systemic delivery remains to be developed for body-wide muscle delivery. However, the improved versions of gutted adenoviral vector may have the potential for local muscle gene therapy to improve life quality.

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