Abstract
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.
Highlights
Viruses are obligate intracellular parasites which have evolved as natural, biological delivery vehicles
Various strategies can be used to generate PEG-modified constructs. These include the use of activated monomethoxypolyethylene glycol (MPEG), which is coupled to proteins using a triazine ring [344], tresylmonomethoxypolyethylene glycol (TM-PEG) which preferentially reacts with ε-amino terminal of lysines [341], or succinimidyl succinate PEG (SS-PEG) which uses the amino reactive N-hydroxysuccinimide (NHS) ester of PEG succinate to couple to target proteins [345]
Chemical modification strategies hold promise for future retargeting strategies, they may have limitations for certain applications, namely the therapeutic treatment of cancer using oncolytic vectors. This is due to the fact that the retargeted polymer coat is not heritable, and unlike genetic modification strategies progeny virions lack the potential for expansive oncolysis via the incorporated targeting ligand
Summary
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 adenoviral 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)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
