Targeted Gene Delivery Using Modified Adenoviruses

Viruses are obligate intracellular parasites which have evolved as natural, biological delivery vehicles. This makes them an attractive choice of vector for various clinical gene therapy applications. Human adenoviruses (Ad) are currently the most widely used viral vectors for gene therapy for several reasons; their basic biology has been studied extensively, the viral genome can accommodate large heterologous transgene insertions, they readily infect quiescent and dividing cells, they can be amplified to high titers and they have previously been shown to be relatively safe for use in humans. The family Adenoviridae consists of five genera, including genus Mastadenovirus and genus Aviadenovirus, which infect mammals and birds respectively. The Adenoviridae are non-enveloped, icosahedral virions which contain a linear, monopartite, double-stranded DNA genome approximately 36 kb in size. As of now, there are at least 55 different human adenoviruses which can be distinguished on the basis of their serological cross-reactivity, hemagglutinating properties or according to their phylogenetic sequence similarity. The adenovirus vector most commonly used for clinical trials and experimental gene therapy applications is species C adenovirus, HAdV-C5 (referred to as Ad5 in this review).

Adenoviruses

Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors. Viruses 2010, 2(10), 2290-2355 doi:10.3390/v2102290
Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated “stealth” vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications.

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3 Responses to Targeted Gene Delivery Using Modified Adenoviruses

  1. Ed Rybicki says:

    I do so hate the word “ablation” used in any other context than in the shedding of outer layers of covering by re-entering space vehicles…but anyway, great post! Nice picture, too: I shall link to it from teaching material soonest.

    But I can’t help thinking of the HIV vaccine trials that recently failed, that used an Ad vector: there’s more going on than we know sometimes, with these relatively big viruses, and their interactions with our immune systems are not fully understood.

  2. AJ Cann says:

    I’m not convinced it’s fair to lay the failure of an HIV vaccine trial at the door of adenovirus though.

  3. Ed Rybicki says:

    Oh, no, you’re quite right – not when it has been pretty convincingly showed that Ad vectors in monkeys confer effective immunity to SIV IF you use the right heterologous combo, AND you have a wide range of T-cell epitope responses to start.

    Which wasn’t the case with the human trial…. One can lay the blame there mainly with a not-particularly-immunogenic set of antigens expressed by the Ad vector – as well, possibly, to the responses to the Ad vector itself.

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