Gene therapy vaccinia

Figure 14.2 Vectors used thus far in gene therapy trials. Others are mainly viral-based and include the use of pox, vaccinia and adeno-associated viruses, as well as herpes simplex virus. Data adapted from www.wiley. co.uk/genemed/clinical...

Gene Therapies. The types of vectors that have been used or proposed for gene transduction include retrovirus, adenovirus, adeno-associated viruses, other viruses (e.g., herpes, vaccinia, etc.), and plasmid DNA. Methods for gene introduction include ex vivo replacement, drug delivery, marker studies, and others and in vivo, viral vectors, plasmid vectors, and vector producer cells. 

Another form of gene therapy to treat cancer involves oncolytic virotherapy. This involves the use of oncolytic vectors, which are virus-designed to home and kill the tumor cells without harming the normal cells in the body. The cancer cells are killed by cell lysis as a result of the production of cytotoxic proteins or due to the propagation of the virus itself. The viruses that have been used to produce oncolytic vectors include adenovirus, vaccinia, reovirus, HSV-1 and Newcastle disease virus. 

Puhlmann M, Brown CK, Gnant M, Huang J, et al. 2000. Vaccinia as a vector for tumor directed gene therapy Biodistribution of a thymidine kinase-deleted mutant. Cancer Gene Ther. 7 66-73. 

Other types of replication-deficient viral vectors that have been used in the gene therapy field include Herpes simplex viral (HSV) vectors that (1) are able to transduce nondividing cells and (2) are highly infective for neurologic tissue and vaccinia vectors. Vaccinia vectors in turn (1) are able to transduce nondividing cells and (2) have the ability to efficiently infect many types of cells. The primary safety concerns for HSV vectors are the potential for tropism to the CNS and the potential for latency and reactivation. Vaccinia vectors contain the same backbone as the smallpox vaccine, thus the available safety databases for vaccinia administration in humans consist primarily of preventive vaccination in a healthy population. Principal safety concerns with the use of vaccinia vectors include (1) their ability to replicate in humans and possibly... 

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. 

Viruses have evolved to achieve robust gene expression within a host s cell. For this reason, viral gene deUvery represents a substantial amount of current gene therapy research, and so far, the best way to deliver a gene to a desired cell type. Viral vector delivery to brain tumors has been investigated using different types of viruses, including adenovirus (Ad), herpes simplex virus (HSV), retrovirus (RV), measles virus, adeno-assodated virus (AAV), Newcastle disease virus (NDV), Semliki Forest virus, vaccinia virus, and reovirus [110]. The most commonly used viruses represented in experimental brain tumor therapies are the HSV and Ad viruses. 

Turunen, P., Puhakka, H.L., Heikura, T, Romppanen, E., Inkala, M Leppanen, 0., and Yla-Herttuala, S. (2006) Extracellular superoxide dismutase with vaccinia virus anti-inflammatory protein 35K or tissue inhibitor of metaDoproteinase-l Combination gene therapy in the treatment of vein graft stenosis in rabbits. Human Gene Therapy, 17, 405—414. 

Qin, H. and Chatteijee, S.K., Cancer gene therapy using tumor cells infected with recombinant vaccinia virus expressing GM-CSF, Hum. Gene Ther., 7,1853,1996. 

Replication- restricted vaccinia as a cytokine gene therapy vector in cancer persistent transgene expression despite antibody generation. Cancer Gen Ther 2000 7 (5) 663-670. 

Other viral vectors have also been developed for use in gene therapy. These include the herpes simplex virus, the vaccinia virus and Sinbis virus. However, these vectors have not been widely studied and it is not clear what advantages they may hold over retroviral, adenoviral or AAV vectors. Recently, limited-replicating viral vectors, such as the Onyx-015 virus, have been developed. The Onyx virus is an ElB deleted adenovirus that can only replicate in p53 deficient cells advantage ofthese vectors is that their replication is limited mainly to tumour cells and that permitting the replication of the virus produces more efficient transfection of the tumour cells. Studies are ongoing to demonstrate the usefulness and safety of replicating vectors. 

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