Herpes simplex viral vectors, gene therapy

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... 

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...

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. 

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. 

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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