Adenoviral vectors for gene therapy

Abstract

Vectors based on human adenovirus serotypes 2 (Ad2) and 5 (Ad5) of species C possess a number of features that have favored their widespread employment for gene delivery both in vitro and in vivo. However, the use of recombinant Ad2- and Ad5-based vectors for gene therapy also suffers from a number of disadvantages. These vectors possess the tropism of the parental viruses, which infect all cells that possess the appropriate surface receptors, precluding the targeting of specific cell types. Conversely, some cell types that represent important targets for gene transfer express only low levels of the cellular receptors, which lead to inefficient infection. Another major disadvantage of Ad2- and Ad5-based vectors in vivo is the elicitation of both an innate and an acquired immune response. Considerable attention has therefore been focused on strategies to overcome these limitations, thereby permitting the full potential of adenoviral vectors to be realized.

In vitro and in vivo studies of adenovirus-mediated human norepinephrine transporter gene transduction to hepatocellular carcinoma

“…27,28 In this study, AdEasy-1 system has been selected for generation of recombinant adenoviruses encoding hNET gene. Compared with traditional adenoviral vectors, the AdEasy-1 system incorporates several unusual features.…”

Gene Delivery Systems: Tailoring Vectors to Reach Specific Tissues

“…An adenovirus (AdV) is a non-enveloped virus formed by an icosahedral protein capsid surrounding a lineal double-stranded DNA of 36 kb (Douglas, 2007). The AdV capsid is characterized by the presence of 252 different capsomers and long fibers protruding from each of the twelve vertices.…”

“…The cell receptor depends on the virus subgroup: A, E and F subgroups use the cell surface coxsackievirus B and adenovirus receptor (CAR); B1 and B2 subgroups use CD46, CD80/86, receptor X, or heparan sulfate proteoglycan (HSPG); C subgroup uses CAR, HSPG, MHC-I, vascular cell adhesion molecule-I (VCAM-I), or integrins; and D subgroup uses CAR, sialic acid, or CD46 (Arnberg, 2009;Campos & Barry, 2007;Sharma et al, 2009). Adenoviral vectors have been used as tools for gene therapy since the late 80s (Friedmann, 1992), and the first clinical trial was started in 1993 (Douglas, 2007). Since then, over 392 clinical trials using AdV vectors have been carried out.…”

“…They have the advantage of inducing high levels of gene expression, are able to infect both diving and nondividing cells, and can be purified to high titers. Furthermore, AdV2 and AdV5 have high bloodstream stability with a reduced risk of insertional mutagenesis, since their genome remains extrachromosomal (Douglas, 2007;Edelstein, 2007;Volpers & Kochanek, 2004). Nonetheless, several drawbacks have been identified during in-vivo evaluation of these vectors: (i) presence of pre-existing antibodies that rapidly neutralize the vector, (ii) after intravenous administration the vector is mainly taken up by liver cells, limiting the vector to reach its target tissue in adequate concentrations, and (iii) use of high doses in an effort to overcome these problems has not proven to be an adequate and safe approach (Arnberg, 2009).…”

Modified recombinant adenoviruses increase porcine circovirus 2 capsid protein expression and induce enhanced immune responses in mice

“…The adenovirus (Ad) expression system, one of the most widely-used viral expression systems, shows more advan-tages than other systems, such as easy construction, higher efficiency of gene transfer, higher titers and induction of humoral, mucosal and cellular immune responses (Benihoud et al, 1999;Douglas, 2007;Ferreira et al, 2005;Kovesdi et al, 1997;Thacker et al, 2009). Adenovirus vector system expressing PCV2 Cap protein has been studied, but has limited immune efficiency (Wang et al, 2006(Wang et al, , 2007.…”