Vectors poxvirus

Most vaccine vectors developed to date are viral based, with poxviruses (as well as picorna viruses and adenoviruses) being used most. In general, such recombinant viral vectors elicit both... 

There is a wide variety of vectors used to deliver DNA or oligonucleotides into mammalian cells, either in vitro or in vivo. The most common vector systems are based on viral [retroviruses (9, 10), adeno-associated virus (AAV) (11), adenovirus (12, 13), herpes simplex virus (HSV) (14)] andnonviral [cationic liposomes (15,16), polymers and receptor-mediated polylysine-DNA] complexes (17). Other viral vectors that are currently under development are based on lentiviruses (18), human cytomegalovirus (CMV) (19), Epstein-Barr virus (EBV) (20), poxviruses (21), negative-strand RNA viruses (influenza virus), alphaviruses and herpesvirus saimiri (22). Also a hybrid adenoviral/retroviral vector has successfully been used for in vivo gene transduction (23). A simplified schematic representation of basic human gene therapy methods is described in Figure 13.1. 

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. 

The first viral vector systems were developed more than 25 years ago [9], and since then viral gene therapy strategies has been progressively developed [10]. A variety of virus vectors has been employed and modified to deliver genes to cells to provide either transient, such as adenovirus [11-13], poxviruses (vaccinia) [14], or herpes virus [15], or permanent, such as retroviruses (lentivirus) [16-18] and adeno-associated virus [19], transgene expression each approach has its characteristic advantages and disadvantages. 

Moroziewicz D, Kaufman H L (2005). Gene therapy with poxvirus vectors. Curr. Opin. Molec. Therapeuti. 7 317-325. 

Poxvirus vectors encompass vaccinia derived from the smallpox vaccine and more attenuated variants like ALVAC or MVA (Modified Vaccinia Ankara). Their genome consists of single-stranded DNA of 130 to 300 kb pairs. Replication is restricted to the cytoplasm of cells and high amounts of protein are synthesized by the cell following transduction. Most applications therefore involve intramuscular vaccination. 

Panicali, D., and Paoletti, E. (1982) Construction of poxviruses as cloning vectors Insertion of the thymidine kinase from herpes simplex virus into the DNA of infectious vaccinia virus. Proc. Natl. Acad. Sci. USA 79, 4927-4931. 

Adeno-associated viruses have been associated with only a small proportion of all clinical trials. Other vectors have used naked plasmid DNA, vaccinia, and other poxviruses, as well as other types of viruses. 

Hu, Y. et al., Yaba-Uke disease virus an alternative replicating poxvirus vector for cancer gene therapy. J. Virol, 75,10300,2001. 

Mastrangelo MJ, Eisenlohr LC, Gomella L, Lattime EC. Poxvirus vectors orphaned and under appreciated. J Clin Invest 2000 105(8) 1031-1034. 

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