02 BOOK OF ABSTRACTS .indd

Electrogenetherapy in cancer
Franck Andre, Lluis M. Mir
UMR 8121 CNRS - Institut Gustave Roussy, Villejuif, France
Gene therapy basic principle is the introduction of nucleic acids into cells in order to
obtain a therapeutic effect. Originally it was meant to correct hereditary monogenetic
diseases but nowadays cancer diseases are the main indication, (67% of the clinical
trials made between 1989 and 2006 [1]). The major limitation of gene therapy is the
vector used for the transfer. Viruses, with their natural ability to infect the cells represent
the most used approach in gene therapy (≈ 70% of current clinical protocols [1]). Due
to adverse events in gene therapy clinical trials using adenovirus or retrovirus, there
was a need for nonviral vectors. Electrogenetherapy is one of the most promising
nonviral approaches.
Electrogenetherapy, or DNA electrotransfer, is the in vivo application of the in vitro
cell transfection approach initiated by Neumann in 1982. Electrogenetherapy includes:
(i) the injection of a DNA or RNA sequence either locally or intravenously, (ii) the
delivery of electric pulses to the targeted tissue, allowing the reversible permeabilisation
of the targeted cells and the penetration of the nucleic acids into these permeabilised
cells, (iii) gene expression or gene silencing.
Although the main target of the therapy is the cancer cell, for electrogenetherapy in
cancer there are two possible approaches: a) to transfect the tumor cells themselves,
or b) to transfect muscle cells and to use the muscle as a factory to produce circulating
molecules that will act on distant tissues (e.g. the tumor). Indeed, muscle is a tissue
that can be very efficiently and reproducibly transfected, while transfection efficacy
may vary from tumor to tumor.
Whatever the transfected tissue, we have shown that the speed and volume of the
injection
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can affect nucleic acid distribution and transfer efficacy. We have shown
that the electric pulses have two roles, a) to permeabilize the target cells and b) to
electrophoretically push the nucleic acids towards the target cells [2]. The combinations
of high voltage microsecond squared pulses (HV) with low voltage millisecond squared
pulses (LV) allow to adjust the delivered pulses to the needs of the electrotransfer.
Even though several kind of pulses have been used, we have found that very high
efficacy and very reduced toxic effects (cellular stress or histological damages) are
obtained using HV + LV combinations of pulses. The optimal parameters (amplitude,
duration, number) of the HV and LV pulses depend on the target tissue.
A wide range of type of nucleic acid have been electrotransfected to treat cancer:
from plasmid DNA expressing local suicide gene in transfected tumor cells or plasmid
coding for antiangiogienic secreted factor in muscular transfected cell, to siRNA
silencing known oncogene in the tumor cells. The results obtained in these preclinical
studies show that electrogenetherapy is a promising approach for cancer treatment.
1. (http://82.182.180.141/trials/index.html)
2. Satkauskas, S., et al., Electrophoretic Component of Electric Pulses Determines
the Efficacy of In Vivo DNA Electrotransfer. Hum Gene Ther, 2005.