Adeno-associated viral vectors

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...

A number of additional viral types may also prove useful as vectors in the practice of gene therapy. Chief amongst these are the adenoviruses. Adeno-associated virus, the herpes virus, and a number of other viruses, are also being considered (Table 14.2). 

Additional viruses that may prove of some use as future viral vectors include adeno-associated virus and herpes virus. Adeno-associated virus is a very small, single-stranded DNA virus its genome consists of only two genes. It does not have the ability to replicate autonomously and can do so only in the presence of a co-infecting adenovirus (or other selected viruses). 

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. 

Viral Vectors. The direct administration of a viral vector (e.g., retrovirus, adenovirus, adeno-associated virus, herpes, vaccinia) to patients. 

Recently another novel method has been described for factor VIII gene transfer in patients with hemophilia A that avoids the use of viral vectors. The transfer was safe and well tolerated, and provided a modicum of benefit [8], Up until now the most promising strategy for factor VIII gene transfer had relied on adeno-associated virus (AAV). 

Adeno-associated virus is the most innocuous of viral vectors. It is nonpathogenic and its genome can be engineered to only encode for the therapeutic gene. There... 

Chao, H., Y. Liu, I Rabinowitz, C. Li, R.I Samulski, and C.E. Walsh, Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol Ther, 2000. 2(6) 619-23. 

Ma, H.I., S.Z. Lin, Y.H. Chiang, I Li, S.L. Chen, Y.P. Tsao, and X. Xiao, Intratumoral gene therapy of malignant brain tumor in a rat model with angiostatin delivered by adeno-associated viral (AAV) vector. Gene Ther, 2002. 9(1) 2-11. 

Bnrton, M., H. Nakai, P. Colosi, I Cnnnmgham, R. Mitchell, and L. Conto, Coexpression of factor VIII heavy and light chain adeno-associated viral vectors produces biologically active protein. Proc Natl Acad Sci USA, 1999. 96(22) 12725-30. 

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. 

Auricchio, A., Behling, K.C., Maguire, A.M., et al. (2002). Pharmacological regulation of protein expression from adeno-associated viral vectors in the eye. Mol. Ther., 6, 238-242. 

Su, H., Lu, R. and Kan, Y.W. (2000) Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart. Proc. Natl. Acad. Sci. USA, 97, 13801-13806. 

Xu, L., Daly, T., Gao, C., Flotte, T.R., Song, S., Byme, B.J. et al. (2001) CMV-/ -actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor la promoter and results in therapeutic levels of human factor X in mice. Hum. Gene Then, 12, 563-573. 

Yang, Y.-W. and Kotin, R.M. (2000) Glucose-responsive gene delivery in pancreatic islet cells via recombinant adeno-associated viral vectors. Pharm. Res., 17,1056-1060. 

Carter PJ, Samulski RJ (2000) Adeno-associated viral vectors as gene delivery vehicles. Int J Mol Med 6(1) 17-27... 

Martin KR, Klein RL, Quigley HA (2002) Gene delivery to the eye using adeno-associated viral vectors. Methods 28(2) 267-275... 

In general, adenoviral vectors are known to infect the target cells effectively, but it is noteworthy to keep in mind that safety always comes first because some adverse side effects could be critical to the health of patients. Other types of viral vectors, such as adeno-associated virus, also are used for gene therapy in many diseases, even though more studies on safety, as well as efficacy, still remain until successful human clinical use can be expected. As demonstrated by clinical reports, fusion of knowledge on the molecular biology of viral vectors and the diseases to be treated holds promises for the future of medicine. 

The strategies just described are in principle also applicable to other viral vectors, and a number of studies describing such approaches have been published, mainly for adeno-associated viruses (AAV) [45-47] and retroviruses [48-50], It can be anticipated that this field will rapidly expand as the mechanisms of virus-host cell interactions are unraveled in detail. 

J. F. Zhou, E.F. Vanin, and A.W. Nienhuis. 2001. Factors influencing in vivo transduction by recombinant adeno-associated viral vectors expressing the human factor IX cDNA. Blood 97 1258-1265. 

ADENO-ASSOCIATED VIRAL VECTORS FOR GENE THERAPY... 

---