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Non-viral Gene Therapy (Overview)

In diseases that currently cannot be cured, one major goal of pharmaceutical research is to replace symptomatic treatments by eliminating the cause of disease. Many ailments are caused by errors found at the genetic level; these are either inherited (such as enzyme defects in metabolic disorders) or are due to mutations that may occur in the course of a lifetime (such as in many malignancies that may be initiated by being exposed to occupational hazards). The concept of somatic gene therapy aspires to replace such defective genes within the affected cells by their genetically intact counterparts. In this case, rather than intervening at the germ-line level only the diseased cells are treated.

Due to their size and charge, it usually is impossible to introduce genetic material (DNA) and RNAs into cells; yet this can be achived by employing suitable carrier systems. These are best combined with the nucleic acid so as to be entered as efficiently and specifically as possible into the respective type(s) of cells (i.e., gene transfer). Such carrier systems take advantage of natural cellular transport mechanisms such as endocytosis. It is however important to consider that, subsequent to cellular uptake, the nucleic acids are protected within the lysosomes from being attacked enzymatically, which would render them useless.

The different carrier systems can be subdivided into viral and non-viral vectors. Viruses are characterized by their property to specifically enter suitable host cells for their propagation. Gene therapy takes advantage of retroviruses, adenoviruses and adeno-associated viruses in which the viral component is replaced by the therapeutic gene or RNA, respectively. Despite their high efficiency,  there is only little prospect for in-vivo applications of these viral systems as the safety of their production and employment are insufficient, which is furthermore exacerbated by the fact that applications are usally followed by the mounting of immune responses that render further applications virtually impossible. As a consequence of various incidents, the field of viral gene therapy is monitored particularly intensely by the authorities.

A group led by Professor Dr. Regine Süss, develops suitable non-viral systems for gene transfer. These include liposomes, lipid / DNA aggregates, lipid / siRNA aggregates as well as polymersomes, polymer / DNA aggregates and polymer / siRNA aggregates. Next to the uptake of DNA, they are examining the transfer of siRNA species that can block the biosyntheses of their corresponding protein products. The optimization of the carriers that, inter alia, includes the specification of gene delivery systems by their modification with selective ligands (active targeting), and the elucidation of the cellular uptake mechanisms has been and is still pursued in various projects in the form of dissertations and postdoctoral engagements (Dr. Christine Schroer in collaboration with Roche Diagnostics GmbH, Mannheim, Germany; Dr. Beate Lubrich, Dr. Reza Eivaskhani, Dr. Susanne Wieland-Berghausen, Dr. Thomas Dern, Dr. Ansgar Wieschollek, Dr. Karin Kiefer and Dr. Jule Clement in collaboration with Boehringer Ingelheim Pharma GmbH und Co. KG, Biberach, Germany; Dr. Stefanie Häfele, Dr. Christian Schifter, Dr. Holm Schmidt in collaboration with Merckle Ulm, Germany; as well as Dr. Sebastian Schneider, Dr. Stefanie Striepe, Dr. Joanna Adrian, Dr. Annette Steinbach, and Doris Zimmer).
One important aspect within these projects is the upscaling of the methods from laboratory to industrial scaling as well as the GMP-compliant production of lyophilized end products. Liposome preparation, cell culture, transfection studies and analytical works are supported by Birgit Erhard.

 

Schneider S, Lenz D, Holzer M, Palme K, Süss R: Intracellular FRET analysis of lipid/DNA complexes using flow cytometry and fluorescence imaging techniques, J. Control. Release, 145(3), 289-96, 2010. [Epub]

Schneider S, Süss R: Spectral bio-imaging and confocal imaging of the intracellular distribution of lipoplexes, Methods Mol. Biol. 606, 457-467, 2010. [Epub]

Huth US, Schubert R, Peschka-Süss R: Investigating the uptake and intracellular fate of pH-sensitive liposomes by flow cytometry and spectral bio-imaging, J. Control. Release 110, 490-504, 2006. [Epub]

Clement J, Kiefer K, Kimpfler A, Garidel P, Peschka-Süss R: Large-scale production of lipoplexes with long shelf-life, Eur. J. Pharm. Biopharm. 59, 35-43, 2005. [Epub]

Kiefer K, Clement J, Kimpfler A, Garidel P, Peschka-Süss R: Transfection efficiency and cytotoxicity of several nonviral gene transfer reagents in human smooth muscle and endothelial cells, Pharm. Res. 21, 1009-1017, 2004. [Epub]

Huth U, Wieschollek A, Garini Y, Schubert R, Peschka-Süss R: Fourier transformed spectral bio-imaging for studying the intracellular fate of liposomes, Cytometry Part A 57A, 10-21, 2004. [Epub]
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