Adeno-associated virus vectors

Nonintegrating Vectors Derived from Adenovirus, Adeno-Associated Virus,... 

The small adeno-associated virus (AAV) vectors can be easily prodnced, have not been found to canse major toxicity, and persist in the transduced hepatocyte typically as an episomal transcriptionally active DNA molecule. Because of the limited packaging capacity for foreign DNA of 4.6 kb, these vectors have been preferentially nsed to express small transgenes and shRNAs directed against HBV or HCV... 

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. 

For loss-of-fundion mutations gene replacement therapy usng retroviruses, adenoviruses, adeno-associated viruses, or liposomes as vectors... 

Two types of DNA viruses have also been used in human gene therapy trials. Adenoviruses, double-stranded DNA viruses, can efficiently carry a larger gene into cells even if they are not dividing, but the genetic information does not become inserted into the cell s genetic material and the information may rapidly be lost. Adeno-associated virus vectors, made from small single-stranded... 

D) Adeno-associated virus (AAV) vector delivered to skeletal muscle... 

Manning, W.C., X. Paliard, S. Zhou, M. Pat Bland, A.Y. Lee, K. Hong, C.M. Walker, J.A. Escobedo, and V. Dwarki, Genetic immunization with adeno-associated virus vectors expressing herpes simplex virus type 2 glycoproteins B and D. J Virol, 1997. 71(10) 7960-2. 

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... 

Wu, P, W. Xiao, T. Conlon, I Hnghes, M. Agbandje-McKenna, T. Ferkol, T. Flotte, and N. Muzyczka, Mutational analysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism. J Virol, 2000. 74(18) 8635 7. 

Ried, M.U., A. Girod, K. Leike, H. Buning, and M. Hallek, Adeno-associated virus capsids displaying immunoglobulin-binding domains permit antibody-mediated vector retargeting to specific cell surface receptors. J Virol, 2002. 76(9) 4559-66. 

Song, S., M. Scott-Jorgensen, I Wang, A. Poirier, I Crawford, M. Campbell-Thompson, and T. Flotte, Intramuscular administration of recombinant adeno-associated virus 2 alpha-I antitrypsin (rAAV-SERPINAl) vectors in a nonhuman primate model safety and immunologic aspects. Mol Ther, 2002. 6(3) 329. 

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. 

Davidson, B.L. (2000). Recombinant adeno-associated virus type 2,4, and 5 vectors transduction of variant cell types and regions in the mammalian central nervous system. Proc. Natl. Acad. Sci. U.S.A., 97, 3428-3432. 

Okada, H., Miyamura, K., Itoh, T., et al. (1996). Gene therapy against an experimental ghoma using adeno-associated virus vectors. Gene Ther., 3, 957-964. 

Flotte TR, Carter BJ. 1997. In vivo gene therapy associated with adeno-associated virus vectors for cystic fibrosis. Adv. Pharmacol. 40 85-101. 

Song S, Morgan M, Ellis T, Poirier A, et al. 1998. Sustained secretion of human-alpha-1 -antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Nat Acad Sci. 95 14384-14388. 

Tsai TH, Chen SL, Xiao X, Chiang YH, et al. 2006. Gene therapy of focal cerebral ischemia using defective recombinant adeno-associated virus vectors. Front Biosci. 11 2061-2070. 

Xiao W, Chirmule N, Berta SC, McCullough B, et al. 1999. Gene therapy vectors based on adeno-associated virus type 1. J Virol. 73 3994-4003. 

Inoue, T., Yamaza, H., Sakai, Y., Mizuno, S., Ohno, M., Hamasaki, N. et al. (1999) Position-independent human beta-globin gene expression mediated by a recombinant adeno-associated virus vector carrying the chicken beta-globin insulator. J. Hum. Genet., 44, 152-162. 

Ohi, S., Dixit, M., Tillery, M.K. and Plonk, S.G. (1990) Construction and replication of an adeno-associated virus expression vector that contains human beta-globin cDNA. Gene, 89,279-282. 

Kunke, D., Grimm, D., Denger, S., Kreuzer, J., Delius, H., Komitowski, D. and Kleinschmidt, J.A. (2000) Preclinical study on gene therapy of cervical carcinoma using adeno-associated virus vectors. Cancer Gene Then, 7, 766-777. 

Loeb, J.E., Cordier, W.S., Harris, M.E., Weitzman, M.D. and Hope, T.J. (1999) Enhanced expression of transgenes from adeno-associated virus vectors with the woodchuck hepatitis virus posttranscriptional regulatory element implications for gene therapy. Hum. Gene Then, 10, 2295-2305. 

---