Presentation by Prof. Carmeliet
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Proficient professor at the University of Leuven. Assistant Manager of the Centre of Transgene and Gene therapy.
Prof. Carmeliet first talked about the kind of research that is being done in Leuven. This research concentrates on the modification of the genetic information that is contained in the nucleus of human cells in the form of chromosomes and DNA. By modifying the genetic code, through the substitution of the building blocks in the DNA, one can imitate diseases as they occur with people, and this in itself makes it possible to obtain new insights in these diseases and ultimately test new treatments.
For this research they do not make so much use of mice, but zebrafish and tadpoles, because they can be genetically modified in a much quicker way.
About a decade ago, Angiogenesis research, being the formation of new blood vessels, was started in Leuven. The reason for this is that more than 70 different diseases are due to a deficiency or an excess of Angiogenesis. For example, heart failure is due to a deficiency of Angiogenesis, and cancer for example can be a result of an excess of Angiogenesis. In Leuven they were interested in unraveling the genetic code of Angiogenesis and one of the most important factors herein is the protein VEGF (Vascular Endothelial Growth Factors).
Via a video, Prof. Carmeliet shows the role of the VEGF protein in Angiogenesis. The video shows the formation of a small tumor that does not need extra blood vessels in the beginning. After a while the tumor does need extra blood vessels to be able to continue to grow, and at that moment the tumor starts secreting the VEGF protein. When this protein fits on certain receptors in the blood vessels, new blood vessels are being formed, that go to the tumor.
Through genetic testing with the VEGF protein they came to a very remarkable conclusion in Leuven, actually by coincidence. With mice where the values of the VEGF in the blood were slightly reduced, it was found that the mice started having problems with the muscles. From research of the nerve cells and the spinal cord they could diagnose that these mice had the disease ALS.
Because this finding was so remarkable, a larger study on this was conducted with different ALS patients together with Prof. Robberecht. This study indeed revealed that people with a defect in the genetic code of the VEGF protein and therefore had less VEGF in their blood have an increased risk of developing ALS.
Although they do not fully understand yet how low VEGF values in the blood lead to the nerve disease ALS, they do have a proposal of explanation. Low VEGF values would contribute to making the blood vessels defect, so less oxygen reaches the nerve cells, which finally results in the nerve cells gradually dying off. On the other hand they also think that VEGF could have a direct effect on the nerve cells themselves. When there is too little VEGF, we take away an important survival activity from the nerve cell. Both these mechanisms could play an important role in the development of ALS.
Is VEGF now also useful for a new therapy? Prof. Carmeliet shows a few ways of how this has been tested.
On the one hand they can perform a kind of viral gene therapy. The VEGF gene is inserted into a kind of capsule. This capsule can then be injected in different muscles. The injected capsule can then jump over to the end of the nerve cell that innervates the muscle and can then be transported in the reverse direction to the cell body of the motor neuron of the nerve in the spinal cord. In this way we help the diseased nerve to make a little more VEGF. Via a graphic, Prof. Carmeliet showed that such therapy with mice, that have ALS, has led to an extended life.
Also with a different kind of viral gene therapy, that works slightly different, they could establish an extended life, which proves that giving VEGF has a useful effect.
Gene therapy however has its restrictions. Therefore one has wondered if one could administer the protein itself. First they diagnosed that the administration via the arm or in the abdomen, or via the muscles, led to a reaction of the body that perceived this protein as unfamiliar and broke off the protein.
Another way was to inject the protein directly in the cavities of the brain. A catheter was placed in the brains of rats, connected to a pump, which allowed for the protein to be administered for extended periods of time. Prof. Carmeliet shows in a video how these rats do better in a test on rolls, than the control rats that have not been administered the protein. Also examination of the nerve cells in the spinal cord of these rats, showed that more nerve cells were present in the spinal cord, then with the control rats.
Now it has been found that with some ALS patients the disease starts with the degradation of the muscles in the lower limbs while with other patients the disease starts with the degradation of the muscles of the tongue and the respiration. Also with the ALS rats it was found that with some animals the disease started at the forelegs and with others at the back legs. It showed that administering VEGF had a beneficial effect on both types of ALS rats.
Prof. Carmeliet ended up with a scheme of what VEGF does. One namely thinks that VEGF has an effect, not only on the motor neuron nerves in the spinal cord, but also on the other types of nerve cells in the spinal cord, such as the so-called support cells. Furthermore VEGF can also have a beneficial effect on the blood vessels and the supply of oxygen to the sick motor neuron. The research in Leuven is focusing now on the better understanding of these mechanisms, so that better methods of treatment can be proposed in the future.
Prof. Carmeliet finally summarizes that the research in Leuven has shown the connection between decreased values of VEGF in the blood and the disease ALS, and that increasing the VEGF values in laboratory animals cannot stop the disease but slow it down. In the future, this research around VEGF will be continued in Leuven with some industrial partners, in phases as prescribed by law. At the moment, for example, they are testing if administering VEGF to bigger animals is safe. Prof. Carmeliet emphasizes that this research is essential, and that only afterwards hopefully the clinical trials with VEGF can be started.
Translation: Tina
