The potential of toxin-based drug delivery systems for enhanced nucleic acid therapeutic delivery

ABSTRACT

Introduction: The potential of gene replacement therapy has been underscored by the market authorization of alipogene tiparvovec (Glybera) and GSK2696273 (Strimvelis) in the EU and recombinant adenovirus-p53 (Gendicine) in China. Common to these systems is the use of attenuated viruses for ‘drug’ delivery. Whilst viral delivery systems are being developed for siRNA, their application to antisense delivery remains problematic. Non-viral delivery remains experimental, with some notable successes. However, stability and the ‘PEG dilemma’, balancing toxicity and limited (often liver-tropic) pharmacokinetics/oharmacodynamics, with the membrane destabilizing activity, necessary for nucleocytosolic access and transfection remain a problem.

Areas covered: Here we review the use of attenuated protein toxins as a delivery vehicle for nucleic acids, their relationship to the PEG dilemma, and their biological properties with specific reference to their intracellular trafficking.

Expert opinion: The possibility of using attenuated toxins as antisense and siRNA delivery systems has been demonstrated in vitro. Systems based upon attenuated anthrax toxin have been shown to have high activity (equivalent to nucleofection) and low toxicity whilst not requiring cationic ‘helpers’ or condensing agents, divorcing these systems from the problems associated with the PEG dilemma. It remains to be seen whether these systems can operate safely, efficiently and reproducibly, in vivo or in the clinic.

KEYWORDS:

• Antisense
• drug delivery
• Endocytosis
• gene therapy
• siRNA
• toxin

Article highlights

• The deferential between the challenges associated with gene and siRNA /antisense delivery.

• Why this differential is important within the context of existing rate limits to non-viral therapy i.e. the PEG dilemma.

• The use of protein toxins as part of non-viral DNA delivery systems.

• How toxins navigate the endomembrane system.

• Recent successes using toxins to deliver siRNA and antisense oligonucleotides.

This box summarizes key points contained in the article.

Declaration of interest

SCW Richardson has shares in Intracellular Delivery Solutions (IDS) Ltd and is the CSO of IDS Ltd. PDR Dyer has shares in IDS Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

SA Shorter thanks the University of Greenwich for funding her PhD. He would also like to thank Greenwich University Enterprises (GUEL) Ltd for funding. MAM Gorringe-Pattrick and AS Gollings thank the University of Greenwich for funding their PhD studies. JE Coakley would like to thank GUEL for funding her PhD.