Genetic modification of viruses has been used for many years as a strategy to treat and prevent different types of diseases. In essence, it is about using certain viral characteristics to build vaccines, or to recognize and attack specific cells (for example, tumor cells). To do this, it is crucial to have space within the viral genome to load the necessary genetic tools without compromising the virus’ survival or affecting the capabilities of interest. Since the viral genome is very compact, until now it has been a genetic engineering challenge to modify virus genetically in an effective way.
Now, a team of researchers from IDIBELL and the University of Barcelona has identified new regions within the viral genome where several genetic sequences can be introduced at the same time in a stable and safe way. In the study, recently published in the scientific journal Molecular Therapy Oncology, they explain how this would allow the insertion of multiple therapeutic genes without losing effectiveness, favoring the design of optimal viral vectors for vaccination strategies or anti-tumour therapy.
More space to combine therapies and increase success
This advance is fundamental for the design of a new generation of cancer treatments that combine several strategies in a single vector. The possibility of combining different anti-tumour mechanisms in a single therapy optimizes the treatment and makes it more complete, possibly overcoming resistance to current treatments. “Thanks to the identification of new insertion points, we will be able to design viruses armed with more tools against cancer: they will be able not only to selectively destroy tumor cells, but also to attack the tumor on different fronts and reactivate the patient’s immune system to help in the tumor elimination” explains Dr. Juan José Rojas, principal investigator of the Immunity, Inflammation and Cancer group at IDIBELL and also researcher at the UB. “It’s about being able to design a Trojan horse with enough space to carry all the weapons needed against cancer”.
Beyond cancer, this discovery has other high-value clinical applications. “Basically, what we have achieved is to find more space to load more useful genetic information, and this is both applicable in cancer and in vaccine design, since this virus is also used as a vaccination vector,” says Dr. Rojas.
Precision genetic engineering within the Vaccinia virus
The Vaccinia virus, where the new insertion regions have been identified, is well known in clinical research. Historically it was the basis of the first vaccine, against smallpox, and has become one of the most promising tools of virotherapy. One of the advantages of the vectors derived from it are their great capacity to host external DNA, which can allow the combination of multiple therapeutic transgenes. However, its highly compact genome limits the regions that can be used to introduce entire functional genes.
IDIBELL and UB researchers, thanks to bioinformatic analysis of the genome of this virus, have shown that two intergenic regions (D10R-D11L and E8R-E9L), between genes, hitherto unexplored, are ideal points for the insertion of therapeutic genes or transgenes of interest. Not only are they very stable areas, but they were able to verify in the laboratory that the introduction of gene sequences did not alter the stability of the vector.
The identification of these new insertion points lays the foundations for a new generation of higher capacity vectors. Already identified, it will now be necessary to work on the development per se of the new vectors for various clinical applications.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research center established in 2004 specialized in cancer, neuroscience, translational medicine, and regenerative medicine. It counts on a team of more than 1.500 professionals who, from 73 research groups, publish more than 1.400 scientific articles per year. IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona, and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).