Cardiovascular diseases (CVDs) are often worsened by the presence of high amounts of reactive oxygen species (ROS), extremely excitable molecules the organism is unable to get rid of, which trigger a condition of oxidative stress. Despite the existence of endogenous defenses, these natural protecting mechanisms become more and more powerless as the situation aggravates.

To boost the process that could oppose noxious oxidative processes, EVGN scientists Seppo Ylä-Herttuala and Anna-Liisa Levonen, from the Gene Therapy Unit at Kuopio Hospital (Kuopio, Finland) and colleagues, decided to build a “controllable vector”, that is a shuttle-molecule that activates only in response to endogenous stressor signals. Then they equipped it with a therapeutic gene coding for an enzyme sensitive to stressful stimuli as well. Due to its “anti-inflammatory properties”, the vector succeeded in inhibiting a set of reactions that end up with the production of pro-inflammatory compounds. The study was published online by the journal Gene Therapy and represents a promising strategy, albeit in its infancy, in the research against CVDs.

“When using gene therapy vectors [molecules that delivery a curative gene to a cell] – explains professor Ylä-Herttuala, who is vice Director of the Department of Biotechnology and Molecular Medicine – the ability to control the therapeutic gene is of critical importance. For this reason, we chose to devise our shuttle vector in a way that it could activate only when endogenous, stressor signals are present. In doing so we skipped the need to intervene with drugs or other external modulators for the activation of the vector, avoiding at the same time the continuous (hence uncontrollable) expression of our gene, which is typical of previous traditional gene therapy attempts”.

What are the features of such a vector? As explained in their paper, EVGN scientists took a promoter sequence called ARE (antioxidant response element) which is known for the ability to switch on antioxidant and cytoprotective genes. Then coupled it to a therapeutic gene called HO-1 (heme oxygenase, encoding for an enzyme endowed with anti-inflammatory properties) and tested the vector on specific cell cultures, in a condition of oxidative stress. “Consistent with our assumption - points out Ylä-Herttuala – the vector produced high amounts of HO-1 thus inhibiting a biochemical pathway leading to the production of inflammatory molecules”.

On the spur of these results, the EVGN team is now turning to animal models to validate this strategy also in vivo.

Full article is: Oxidative stress-inducible lentiviral vectors for gene therapy
H Hurttila, J K Koponen, E Kansanen, H-K Jyrkkänen, A Kivelä, R Kylätie, S Ylä-Herttuala and A-L Levonen
Gene Therapy advance online publication 1 May 2008; doi: 10.1038/gt.2008.75

S Ylä-Herttuala