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Steroid mediated gene delivery: focus on androgens

English title Steroid mediated gene delivery: focus on androgens
Applicant Frey-von Matt Brigitte
Number 107870
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Experimental Cancer Research
Start/End 01.09.2005 - 31.07.2009
Approved amount 229'833.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Molecular Biology

Keywords (6)

Gene therapy; PNA; prostate cancer; bladder cancer; androgens; androgen receptor

Lay Summary (English)

Lead
Lay summary
The use of gene therapy to treat genetic disease states has increasingly become the focus of research. The ideal gene delivery system should have at least the following characteristics: the ability to target cells specifically, the capacity to transduce a large number of cells regardless of their mitotic status, and the potential to be synthetic and of low toxicity.Recently we have developed a new procedure to transfer genes. We proposed to target nuclear steroid receptors to achieve a receptor-dependent enhanced expression of transgene DNA. This strategy, termed steroid-mediated gene delivery (SMGD), facilitates the nuclear uptake of transfected DNA with the help of glucocorticoid receptors (GR). Nuclear receptors such as GR are natural cytoplasm-nucleus shuttles that have been proposed to actively trafficking via interacting with microtubuli. To this aim we synthesized a construct consisting of the synthetic steroid dexamethasone, a chemical spacer and a DNA-binding moiety, which was finally coupled to a reporter gene. The first DNA-binder was psoralene {Rebuffat et al, Nat Biotechnol. 2001 Dec; 19(12): 1155- 1161} and the optimized version contained peptide nucleic acid (PNA) {Rebuffat, FASEB J. 2002 Sep; 16 (11): 1426-1428}. Using this ligand-DNA-construct we showed that cells translocated and expressed transgene DNA. The transport and expression was specific for cells with, but not cells without GR, an effect even more pronounced in growth arrested than in proliferating cells. These results were the first proof of principle, that a chemically modified steroid ligand can be used for cell specific DNA delivery in vitro. A patent covering this strategy was accepted in Australia, New Zealand, USA, and Europe and is in the nationalization phase in Japan, Canada. In the present application we propose to target androgen receptors (AR) by SMGD. For that purpose we propose to synthesize steroid derivatives consisting of various androgen moieties. We plan to perform receptor-binding studies, translocation and transactivation assays using cells with different expression levels of AR. If successful, the present investigation will enhance the trafficking of DNA from the cytoplasm to the nucleus in AR-expressing cells, an effect with potential utility for clinical applications aiming at the selective macromolecular treatment of target tissues that express AR such as prostate or bladder cancer.
Direct link to Lay Summary Last update: 21.02.2013

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