Adenovirus adenoviral expression

There are a number of other potential targets for gene transfer in ALI/ARDS. Adenoviral vector-mediated expression of atrial natriuretic peptide in rat lung airway and alveolar epithelium reduced development of pulmonary hypertension after hypoxic challenge (212). Adenovirus-mediated expression of a neutrophilic elastase inhibitor has been demonstrated in rat lung but not yet evaluated for efficacy in acute lung injury (213). Cationic liposome-mediated expression of Oj-antitrypsin in cultured CF bronchial epithelial cells decreased injury result-... 

While short-term, high-level gene expression may be appropriate for some gene therapy applications, it would be of less use for the treatment of, for example, genetic diseases, where long-term gene expression would be required. This could be achieved in theory by repeat administration of the adenoviral vector. However, adenoviruses prompt a strong immune response, which limits the efficacy of repeat administration. 

Each type of virus has different attributes, so several classes of animal viruses are being engineered as vectors to transform mammalian cells. Adenoviruses, for example, lack a mechanism for integrating DNA into a chromosome. Recombinant DNA introduced via an adenoviral vector is therefore expressed for only a short time and then destroyed. This can be useful if the objective is transient expression of a gene. 

Furthermore, infection of adult rat myocytes with adenoviral vectors containing either wild-type or L39stop PLN cDNAs indicated that wild type PLN decreased the contractile parameters and calcium kinetics, compared to control cells infected with an adenovirus expression GFP. However, the PLN-L39stop did not alter myocyte mechanics or calcium cycling. 

However, a variety of issues have implications for the use of viral vectors in gene therapy. Obvious potential concerns are the immune and inflammatory responses to viral vectors. Patients who received VEGF-121 via an adenoviral vector had increased levels of serum antiadenoviral neutralizing antibodies, but there was no report on an inflammatory response in these patients (27). The use of adenovirus-mediated gene therapy in treating brain tumors has been reported to lead to active brain inflammation as well as persistent (up to three months after treatment) transgene expression (30). 

The oncolytic viruses include adenovirus, measles, reovirus, vesicular stomatitis virus (VSV),HSV,poxvirus, and vaccinia. Specific examples include (1) ONYX-015, which is an adenoviral oncolytic virus, administered to patients with liver metastases of colorectal cancer and pancreatic cancer [29], (2) Reolysin, which is an oncolytic reovirus administered to patients with glioma [30], and (3) MV-CEA, which is an oncolytic measles virus expressing carcinoembryonic antigen, administered to patients with ovarian cancer [31]. Some oncolytic viruses are wild type and are apparently not pathogenic in humans, such as the Newcastle disease virus (NDV), which is an RNA avian paramyxovirus. PV701, a naturally attenuated, replication-competent strain of NDV, has been administered to patients with advanced solid tumors [32], The applicability of oncolytic viruses as a therapy for clinical oncology trials is due to their potential selectivity the ability to kill tumor cells but not normal cells. However, the level of attenuation of viral replication in normal cells is limited for most oncolytic vectors. 

Fig. Z3 Viral vector production. The rAAV Vector plasmid contains the therapeutic gene flanked by the ITRs, usually of AAV2. The helper plasmid contains the rep and cap genes, as well as the adenoviral genes needed for replication. Both plasmids are transiently transfected into HEK293 cells that express the adenovirus ElA and ElB gene products...

Unlike retroviruses, adenoviruses do not integrate into the host genome and thus do not replicate. As a result, genes delivered by adenoviruses are only active temporarily. Adenoviral-mediated gene therapy is employed commonly in cancer patients because permanent gene expression is unnecessary in this patient population. 

---