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Innovative navigation system enables gene shuttles to reach their destination

If everything goes to plan, the Department of Gene Therapy at the University of Ulm will soon lose a work group to industry. Florian Kreppel’s team plans to turn a particular technology into hard cash using a method that can do something other gene shuttles are unable to do, namely transport their freight to a specific destination. The researchers from Ulm recently received 1.7 million euros in funding from the German Federal Ministry of Research and Education (through the Go Bio funding programme) in order to develop their method and their team with the aim of bringing their product to market.

Florian Kreppel has received money to establish his company.

The money will be used to develop a new platform for genetic vaccines. Rather than being based on partial or entire pathogens, these vaccines only involve genetic information that encodes one or several constituents of a specific pathogen. The method used by the team enables the generation of pathogen constituents in the body of a vaccinated individual. Kreppel explains that this leads to far better immune responses than with traditional vaccines.

Prior to Kreppel's invention, the development of an effective vaccine against infectious diseases such as AIDS, malaria and hepatitis C was impossible because the pathogens hide in the cells and the vaccines could not be attached to the immune cells.

Kreppel's technology is now about to solve the transport problem: this technology involves gene shuttles that transport gene fragments to and into appropriate cells where they produce the pathogen constituents and trigger an immune response. Such cells are professional antigen-presenting cells, dendritic cells or macrophages, and not muscle or vessel cells. Kreppel's team uses a number of different vectors, which is why it is appropriate to use the term "platform technology". Deactivated adenoviruses are used as gene shuttles for the vaccines and synthetic polymers such as polycations. The 37-year-old biochemist has spent many years developing an "address label" for these gene shuttles that only targets specialised immune cells, i.e. antigen-presenting cells.

Effective address labels

Scientists had been aware of the problem for a long time, but its technical implementation, i.e. the attachment of a “key” to the vector’s surface so that it fitted into the “lock” of the immune cell, proved to be very difficult. The vector must be labelled in such a way that it does not alter the fragile biological and physical structure of the gene shuttle, Kreppel explains.

Many approaches were tested and many experiments carried out, including the use of peptide ligands, double-specific antibodies or adaptor domains; however, none of these approaches made it further than preclinical studies. Investigations involving chimerical or hybrid vector shuttles failed due to safety considerations. In order to exclude the possibility that the gene shuttles specifically or non-specifically interacted with other tissues or cells, the researchers eventually began to coat the viral particles with polymers.

Kreppel’s concept involves the use of a mild chemical procedure to correctly label the gene shuttles without interfering with their integrity. This method enables the chemical alteration of the adenovirus surface by attaching “address labels” of any size. The approach can be used universally and also works with synthetic polymers and other types of viruses, said the biochemist from Ulm.

The genetic and chemical modification of the capsid surface enables the researchers to attach more accurate “address labels”. © Kreppel, University of Ulm

Minimal genetic modifications provide the surface of the virus particles with new chemical reactivity. This can be achieved through the introduction of thiol groups, which enables the covalent, highly efficient and specific binding of ligands. These address labels can be of varying sizes and can originate from different substance categories. Since the method involves a defined chemical procedure, Kreppel is able to control the position and number of labels that are attached to the surface of the viral particles.

The gene shuttle is injected below the skin or into the muscles. It reaches and attaches to the professional antigen-presenting cells, which then take up the virus particles. The virus particles open up inside the immune cells and release the pathogen’s genetic information. Kreppel explains that although the release of the freight by viral vectors had not previously been a problem and is well known in the field of science, a solution still had to be found for transporting the vectors to their specific target. But thanks to Florian Kreppel, this problem has now been solved.

Learning from limitations

Adenoviruses are increasingly used as vectors as was recently shown by the Second Gene Technology Report of the Berlin-Brandenburg Academy of Sciences. © Kreppel

Kreppel and his team have spent many years testing a broad range of methods to attach specific address labels to the viral particles and they finally found a mild chemical method that worked. Their work provided them with excellent insights into the limitations of the other methods investigated. Based on these insights, we finally came up with an idea to circumvent these limitations and have developed it into a relatively high level of maturity, said Kreppel.

As soon as it was shown that the method worked, Kreppel was immediately convinced of its huge application potential. He was sure that the method was far better than genetic vaccines and also envisages the application of the method in tumour therapy using oncolytic viruses.

The researchers have been focusing on the method since 2003 and they protected essential parts of the invention with patents in 2004. They finally presented the method to the scientific community in 2005. The researchers regard their successful participation in the "Go Bio" start-up competition run by the German BMBF as external recognition of their application-oriented top research.

Establishment of start-up company planned for 2011

Kreppel’s research group hopes to establish a company based on this platform technology in about two years’ time. The biochemist is convinced that they will be able to take the technology to marketability within three years, despite the high risk associated with the foundation of the company. The final proof of the method’s effectiveness will be a “huge breakthrough” in the development of genetic vaccines and would also bring the possibility of effectively combating HIV, malaria and hepatitis C considerably closer.

Kreppel, who strongly believes in his platform technology, is well aware of the fact that the resolution of the transport problem is only one, albeit important, step in the development of genetic vaccines. Mouse models are available, but so far no genetic vaccine has been tested in humans. The gene shuttles used in clinical studies – both in classical gene therapy and genetic vaccination – led to a huge amount of data that suggested that far better “address labels” were required.

Kreppel hopes to be able to convince big pharmaceutical companies of the value of his technology in about two to three years’ time and he is also hoping to subsequently carry out clinical studies in cooperation with future industrial partners. All this means that it will still take a few more years before the first genetic vaccines are available.

Two-pillar model

Kreppel’s business model is based on two pillars. The company hopes to achieve early revenues by licensing the invention to pharmaceutical producers at well as attracting the attention of investors. At the same time, or maybe “slightly later”, the Ulm researchers plan to develop specific product candidates and genetic vaccines against diseases such as malaria.

Florian Kreppel will use the 1.7 million euros that the German government are providing over the next three years to obtain “proof of concept” for the genetic vaccination in the animal model using different model antigens. The money will be used to carry out the necessary experiments and to hire a number of people.

At present, it appears that the members of Kreppel’s team intend to accompany their boss into the world of self-employment. “I have the rare opportunity to turn my scientific results into concrete applications. And I am almost there,” said the future company founder who has already convinced the BMBF reviewers, but who still has to convince many others of the feasibility of his new method.

Kreppel, F., Gackowski, J. et al: Combined genetic and chemical capsid modifications enable flexible and efficient de- and retargeting of adenovirus vectors, in: Molecular Therapy (2005), p. 107-117 (doi:10.1016/j.ymthe.2005.03.006)
Corjon, S., Wortmann, A., et al.: Targeting of adenovirus vectors to the LRP Receptor Family with the high-affinity ligand RAP via combined genetic and chemical modification of the pIX capsomere, in: Molecular Therapy (2008) 16 11, 1813–1824, doi:10.1038/mt.2008.174
Müller-Röber, Bernd et al. (2009): Zweiter Gentechnologiebericht. Analyse einer Hochtechnologie in Deutschland (Forschungsberichte der Interdisziplinären Arbeitsgruppen der Berlin-Brandenburgischen Akademie der Wissenschaften, Vol. 23, p. 173ff.

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