"The new transposon system is able to introduce genes into cells and to stably insert them into the cell's genome at an unprecedented efficiency," Dr. Lajos Mátés, Dr. Zoltán Ivics and Dr. Zsuzsanna Izsvák point out. They worked together with scientists from the Catholic University of Leuven, Belgium (Nature Genetics, doi: 10.1038/ng.343).*
Transposable elements are molecular parasites that propagate themselves in genomes. But at the same time they provide plasticity to the genome that clearly contributed to the evolution of gene function across the tree of life. About half of the human genome is derived from ancient transposable element sequences, Dr. Izsvák remarks.
However, due to mutations, the vast majority of the transposons became inactivated. Based on transposons in fish that are presumed to have been active approximately 20 million years ago, Dr. Ivics and Dr. Izsvák resurrected a jumping gene more than ten years ago. They named the transposon Sleeping Beauty, because they literally awakened it after a long evolutionary "sleep".
With their new tool, they were able to introduce genes into cells of vertebrates which was impossible before, as researchers previously lacked efficient transposon technologies to do so. However, the efficiency of the new transposon remained limited in some cells, such as stem cells.Hundredfold Increase in Sleeping Beauty's Activity
Currently, scientists use disarmed viruses or a variety of non-virus based methods to get genes into cells. However, these methods are either too dangerous or too inefficient for broad application in gene therapy. Experiments with the new transposon system in mice showed that transgenes enter the genome safely and are stably integrated, says Dr. Ivics. Even after a year, the genes were still active.
The MDC researchers hope that their new tool is going to become the new standard method to introduce genes into cells. "Already this year, the first clinical trial with the transposon developed in our lab shall take place in the USA", says Dr. Ivics. According to him, Sleeping Beauty will be used to transport a therapeutic gene into isolated immune cells (T cells). These altered cells will then be used to treat a specific form of cancer (B-lymphoid malignancies) in patients.
The research is part of a project funded by the European Union and coordinated by the MDC. Together with nine partners from seven European countries, the MDC-researchers seek for novel, nonviral technologies for therapeutic gene delivery.
*Molecular Evolution of a Novel Hyperactive Sleeping Beauty Transposase Enables Robust Stable Gene Transfer in Vertebrates
Lajos Mátés1,*, Marinee K. L. Chuah2,*, Eyayu Belay2, Boris Jerchow1, Namitha Manoj1, Abel Acosta-Sanchez2, Dawid P. Grzela1, Andrea Schmitt1, Katja Becker1, Janka Matrai2, Ling Ma2, Esmira Samara-Kuko2, Cony Gysemans5, Diana Pryputniewicz1, Csaba Miskey1, Bradley Fletcher3, Thierry VandenDriessche2, Zoltán Ivics1 and Zsuzsanna Izsvák1,4* Contributed equally
5 Department of Experimental Medicine, Laboratory for Experimental Transplantation, University of Leuven, BelgiumBarbara Bachtler
Barbara Bachtler | Max-Delbrück-Centrum
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