Adenovirus – Clinical
Applications
Applications and Clinical Perspectives
• Ad, especially serotypes 2 and 5, have been tested in many protocols including clinical trials with cancer, α1-anti-trypsin deficiency, cystic fibrosis, coronary artery disease, haemophilia A and B (Gao et al. 2007).
• Recombinant Ad vectors have been rendered replication deficient through deletion of essential viral genes. Deletion of the viral genes allows for insertion of a novel genetic expression cassette, which when transcribed in the target cells, leads to the production of a therapeutic protein.
• Three classes of recombinant Ad vectors have been developed for gene therapy purposes
(Danthinne and Imperiale 2000; Giacca 2010; Khare et al. 2011b; Seregin and Amalfitano 2010).
In first-generation Ad vectors, the transgene expression cassette (8 kilobase – kb) was replaced by E1 and E3 viral genes (Alba et al. 2005). These vectors elicit a significant immune response in vivo, therefore, additional genes necessary for viral DNA replication (E2 and E4) have been
deleted, giving rise to the second generation of Ad vectors that can carry a genetic payload of 14 kb (Danthinne and Imperiale 2000). In the third class of Ad vectors (gutless or helper-dependent Ad), all the viral genes are deleted in order to accommodate multiple transgenes, up to 37 kb (Parks et al. 1996).
Clinical trials
• Ad vectors are being tested for different genetic diseases including cardiovascular diseases, cystic fibrosis and cancer or as vaccines for infectious
diseases (http://www.wiley.co.uk/genmed/clinical).
Despite the ongoing clinical trials, the clinical
efficacy of these vectors has yet to be proven. For cystic fibrosis (CF) for example, despite the
encouraging results in nasal and pulmonary tissues of pre-clinical models and being well tolerated at low-to-intermediate doses in humans,
Examples
• Ad-mediated gene transfer in the absence of epithelial damage has been inefficient in CF patients (Joseph et al.
2001). The use of adenoviral vectors for CF gene therapy is therefore currently limited by low transfection efficiency and inability of repeated administration (Griesenbach et al. 2004).
• Ad vectors have been explored as potential vaccine
candidates for a variety of infectious diseases including
malaria, SARS and HIV infections (Bassett et al. 2011; Thacker et al. 2009). Ad-based vaccines are particularly effective
because high antigen-specific immune responses can be induced against encoded transgenes.
Examples
• Oncolytic virotherapy, on the other hand, is a promising form of gene therapy in cancer that has emerged in the late 1900s. To date, virotherapy has been shown to be safe and has generated clinical responses in tumours that are resistant to chemotherapy or radiotherapy (Choi et al. 2011; Toth and Wold 2010). The
major challenge for the researchers and clinicians is to maximize the efficacy of these viral therapeutics. Ad can be modified in a wide variety of ways to improve their selectivity and efficacy.
The viral genome can be easily engineered to incorporate different tumour targeting mechanisms or therapeutic
transgenes for improved anti-tumour properties (Cody and
Douglas 2009; Eager and Nemunaitis 2011; Pesonen et al. 2010).
