Pharmaceutical Non-Viral Formulations for Gene Vaccines
Ever since the ground-breaking findings that immune responses can be provoked by biolistic application of pDNA and subsequent protein expression, no effort has been spared in order to make genetic vaccination feasible. Unfortunately, most approaches faile
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Pharmaceutical Non-Viral Formulations for Gene Vaccines Glen Perera and Andreas Bernkop-Schnürch
Ever since the ground-breaking findings that immune responses can be provoked by biolistic application of pDNA and subsequent protein expression, no effort has been spared in order to make genetic vaccination feasible. Unfortunately, most approaches failed to convert the promising results from rodents to larger animals and human beings. To make such systems available for a global community, simple, safe and highly effective delivery systems are highly on demand. Since physical methods like the “gene gun” are neither cost-effective nor applicable in an everyday use and viral systems are still subject to heavy safety concerns, chemo-pharmaceutical approaches have become a major area of interest within the field of genetic vaccination. This chapter will shine a light on the barriers that need to be overcome by genetic vaccination systems and on the major approaches to achieve this aim. In particular, approaches based on (cationic) polymers, cationic lipids, combinations of these two major strategies and their in vivo performance will be discussed in detail. Besides, immunostimulatory agents and targeting ligands will be discussed as options to improve the in vivo efficiency of a genetic vaccination system. Finally, alternative routes to intradermal and intramuscular injections will be highlighted as part of future developments in this field.
Introduction Genetic vaccines represent one of the most modern and most valuable contributions to the vaccination area in the past two decades because of their numerous advantageous features like comparably simple customization of the DNA sequence, low
G. Perera (*) Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria e-mail: [email protected] J. Thalhamer et al. (eds.), Gene Vaccines, DOI 10.1007/978-3-7091-0439-2_5, © Springer-Verlag/Wien, 2012
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production costs, high storage stability and their potential to induce robust cellular and humoral immune responses. Ever since Wolff et al. achieved protein expression after intramuscular plasmid DNA (pDNA) application in mice (Wolff et al. 1990) and Tang et al. could demonstrate that an immune response can be induced by proteins which are expressed after biolistic application of pDNA in mice (Tang et al. 1992), it is the aim to make genetic vaccination feasible in humans. Unfortunately, the very promising results from pre-clinical studies in small laboratory animals could not be reproduced in man with naked DNA formulations. Limited efficacy of DNA vaccines may be attributed to extracellular barriers such as nucleolytic degradation or adhesion to non-target tissues. Upon arrival at the target, further barriers like the cell membrane, entrapment in endosomal vesicles and lysosomal degradation as well as the nuclear membrane need to be overcome. A variety of strategies have been developed in order to tackle these problems. Recombinant v
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