Gene therapy is the most innovative therapeutic approach in medicine today. It combines the latest research into genetic technologies to treat both inherited and acquired diseases. Unfortunately, actual therapy is hampered by the lack of a safe and efficient delivery system. Thus, the primary objective of gene therapy is the development of efficient, non-toxic gene carriers that can deliver foreign genetic material into cell types, including cancerous cells.
Such gene carriers are sometimes made of viruses, but non viral systems are largely preferred due to their safety and ease of industrial production. Nowadays, more than 20 per cent of human gene therapy clinical trials worldwide use non viral gene delivery systems. In about 33 per cent of those trials, cationic liposomes are used. These are small spheres made of lipids (molecules that are the main structural components of biological membranes) with diameters 10.000 times smaller than a millimetre, which can bind nucleic acids (DNA, RNA) giving rise to stable complexes usually referred to as ‘lipoplexes’.
Investigating Molecular Mechanisms
Lipoplexes have several advantages over some other delivery methods, but they do not transfer a useful amount of the genic drug into the target cell. The scientific community believes that this low efficiency is essentially the result of a general lack of knowledge about interactions between complexes and cellular components. The time of ‘trial and error’ – when a delivery system was considered good just because it worked and the reasons why it was successful were not investigated at all – is over. We are now trying to understand the mechanisms involved.
Our long-term goal is to learn about the interactions between lipoplexes and living cells, and so develop appropriate carriers for use in therapeutics and disease control. To investigate such molecular mechanisms, the most modern techniques are combined, and ‘transfection efficiency’ – the success of the delivery process – is measured.
In Need of Precise Control
We have already begun this work by preparing, for the first time, lipoplexes made of a combination of lipids which have highly specific chemical–physical properties. This strategy has resulted in genic drug delivery that is up to 100 times more efficient than that obtained by systems generally used. We have found evidence that this efficiency boost is due to a distinctive ability of the prepared systems to protect the DNA and to release it, undamaged, into the nucleus of the cell.
To understand the molecular mechanisms of gene delivery we need to control the lipoplexes precisely, from the point of their creation right up to their arrival in the cell nucleus. In collaboration with scientists from several European institutions, my research group will develop a novel high resolution method to investigate the process of drug delivery.
Manipulating DNA and Lipoplexes
We will be able to control the movement of lipoplexes within cells with lasers, and a specialized microscope will allow us to see the genes being delivered into the cell. At the same time, exceptionally brilliant radiation will reveal the changes that take place in the structure of the lipoplexes as they interact with the cell. This is likely to be the only realistic chance we have of understanding the mechanisms of gene delivery.
Such innovative instrumentation will allow us to manipulate DNA and lipoplexes within living cells and to image lipoplex–cell interactions with an unprecedented level of accuracy. Researchers will then be in a position to design highly efficient carriers, and to develop ground-breaking, potent therapeutics. These will be of huge value to researchers in their quest to take final revenge on cancer and other genetic disease, with the potential of enormous economic and social benefits to us all.