Presentation by Prof. Robberecht
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Professor KU Leuven, UZ Gasthuisberg, researcher Clinical and Experimental Neurology.
Professor Robberecht started out expressing his gratitude for being allowed to join the celebration of the 10th anniversary of the ALS Liga. Today he'll give a more general explanation about ALS and he'll touch a few elements of the research he's doing at KU Leuven.
What is ALS?
ALS causes the motor neurons, located at the front of the spinal cord and which send signals to the muscles, to work inadequately at first, to waste away later on. These motor neurons don't work in on their own however, but are built into a circuit of other telephone lines. The telephone lines start from the brain or the motor cortex. They tell or give orders, coming from the brain, and pass them on to the lower motor neurons which in their turn pass on the command to the muscles to execute certain movements. The latter cells are called upper motor neurons. It's the combination of these 2 motor neurons that's typical for ALS.
The consequence is familiar to us: the muscles that are being supplied by these motor neurons decrease in mass. In 4 out of 5 patients this first happens in one of the limbs (legs or arms). In 1 out of 5 patients the tongue and throat muscles are damaged first.
The more of these motor neurons stop functioning, the bigger the problems for the patient. Going will be hindered, grabbing will be impossible and if the tongue and throat muscles are affected then talking becomes difficult.
How do you get ALS?
This is a question that's difficult to answer. There has to be made a distinction between the familial (10%) and sporadic form (90%) of ALS. In case of familial ALS the disease is inherited by 1 out of 10 patients. If it's the sporadic or non-familial form, no one in the family has ALS. This means the children don't have an increased risk of getting the disease as well.
When it comes to familial ALS one knows the responsible gene or hereditary flaw that causes the disease in 1 out of 5 families. The gene or piece of hereditary material that causes ALS in these cases is decided by a protein we call the SOD1 protein. This is a protein that plays an important part in the cell. However, we don't exactly know how we go from a change in this SOD1 protein to the selective wasting away of the motor neurons. It's important to know that we don't know the cause in the other 4 families. This means we only know the cause from barely 1 or 2% of all ALS patients, which is the SOD1 deviation.
This SOD1 deviation was found in 1993-1994 and had the important consequence that one could start creating mice and rats. After incorporating the hereditary material (coming from a human being) the mouse or rat developed a disease which is a very good example to study ALS. This was the start of thorough scientific research in ALS.
The availability of this mouse and rat indicates that the scientists can also test the possible treatments, of those they ought to be useful.
How you get sporadic ALS, is a very difficult question. It's thought to be a combination of three different factors. First of all it is believed that a hereditary predetermination is in play. Watch out, this is inheriting a certain aptitude, not the disease. This can be compared to aptitude for diabetes or high blood pressure. Now they even think there is a similar aptitude in other diseases of the central nerve system, such as Alzheimer's or Parkinson's disease or multiple sclerosis. These aren't hereditary diseases, but there is a certain aptitude in play here.
Aside from that one thinks the aging process plays a part. Most patients develop the disease around the age of 50, 55. The scientists are just now beginning to discover what aging means. They're beginning to study and understand the aging model.
The environment is the last factor to be considered, but here the professor is on thin ice. Still this is of the utmost importance, because if we can identify the environmental factors, we can also attempt to eliminate them and prevent the disease from starting. The problem, however, is that we don't know these factors. It is believed that certain substances used in dental fillings are damaging, and people who work at a printing office and are exposed to toxic substances could also be more likely to get ALS. This is also said about soccer players. But upon in depth studies this appears not to be true. Yet we should keep this in mind, despite not knowing any factor that could have a hand in it.
Difference in disease duration
Aside from the questions about the disease ALS, the following question is also asked: “How long does the disease last, how much time do you think I have left?” This is something that can't be predicted, despite the fact that you can read on the Internet or somewhere else that the average is 3 to 5 years. This has to be expounded. There are patients who live over 5 years and some even longer than 10 years. There's even a form with an average of 13 years and another form where the patients can live 20 years with it.
PLS or Primary Lateral Sclerosis
With PLS it's not the lower motor neurons that are affected, but only the phone lines that come from the brain are slowly being cut through.
PLS is extremely rare. They say it occurs 10 times less often than ALS. In Belgium there are only 1 in a million who suffer from this disease. This form develops very slowly, is almost never familial and turns into ALS in the first 2 or 3 years.
Research Leuven
There are four different teams that are working on ALS research.
Neurology department – UZ Gasthuisberg
Here they primarily search for hereditary changes, they try out new treatments, do research on the blood flow in the brain of patients with ALS.
Experimental neurology department (see up ahead).
Laboratory of Prof. Carmeliet (see his presentation) concerning the part, toxicity and effect of VEGF in ALS.
Stem cell institute of Leuven led by Catherine Verfaillie
Excitotoxicity: toxic effect of glutamate on motor neurons
What part does glutamate play in the etiology of ALS? When 2 nerves have to talk to each other or pass through a command, it uses a particular substance called glutamate. When there ends up too much glutamate on the motor neuron it can waste away. This is because of the interaction of the glutamate with the receptor. The strange thing about such a receptor is that it lets in calcium. When the motor neuron receives too much calcium, it wastes away. Normally this is cleaned up by glial cells in the nerve system. They suck up the excess of this substance. The composition of this receptor is crucial for developing ALS. It has to be checked why there is a difference in receptors that let through little calcium and the receptors that let through a lot of calcium. With the latter there has to be looked for substances that are held back by this receptor. When we give substances, which the bad receptors hold back, to mice, they live longer and develop ALS in a later stage. It also goes the other way around that with receptors that let through a lot of calcium, you get a very aggressive form of ALS. That's why it's believed that these receptors play a very important part in the development of ALS.
Recent research shows that it aren't the motor neurons, but the glial cells that tell the motor neurons how much the receptor should give. With hereditary forms of ALS these glial cells say what has to happen a lot less and the motor neuron wastes away. The strange thing is that these glial cells don't waste away and instead multiply heavily. In the near future there will be tests of a medicine that will repress this multiplication.
It's important to check what we can do with stem cells in the future. If we should insert these into the spinal cord to take over the part of the lost neuron, we have to keep in mind the many telephone lines that need to be laid out and of which the motor neuron is a part. This is difficult to accomplish. That's why we need to check whether we can't change the glial cells and create a better environment for the motor neurons. By doing this the sick neuron might recover. Hopefully this can soon be tested on mice and rats.
In 2001-2002 there was an experiment in the United States, where the environment of the motor neurons was improved. It looked like the mice became sick less quickly. So this needs more research.
Search for different animal models
When it comes to sporadic ALS (see above) they want to identify the hereditary factors as quickly as possible. They call these risk genes. If you have such a gene, it doesn't mean you'll get ALS. But the risk of getting it increases. Unlike with the familial ALS, where you have the SOD1 gene, if you have the sporadic form you have to look for different genes that are at the base. There are also other genes that have an effect on the first kind of genes. There is even a third kind of genes that in its turn upsets the second kind. This is being researched in association studies. This research is done by using blood samples from ALS patients. They actually look for genes that form a risk and look into as to why one person develops ALS and another person doesn't, despite the fact that they've been living in the same circumstances and environment.
That's why it's important to look at even smaller animal models that are easily manipulated. They multiply even faster than mice and rats. This is the research that is being supported by the ALS Liga. In the United States they thought of the fruit fly, but it didn't develop ALS after inserting the SOD1 gene. That's why in Leuven they're thinking of zebrafish. These multiply fast and they're easy to execute genetic manipulations on. The zebrafish are 3 to 4 centimeters. Because they reproduce fast, you can check genetic changes more quickly. And you can check whether or not these matter when it comes to ALS. This research is still at an early stage, but it's highly anticipated.
10 Years ALS Liga
What has been realized by the Liga until now is impressive to a doctor and/or scientist. Before 1993 there were no ALS centers, no neuromuscular reference centers, there was almost no or no research at all and there was no ALS Liga. There was a research concerning the SOD1 mutations (L38V, G93C) with families where ALS occurred. It's thanks to their cooperation that in 1993 they succeeded to develop the mice models in Boston.
1994-1995: as a result of the myotropic study, ALS Liga was founded.
1995-2005: the Liga has developed into a point of support for information (publications, Internet, …), logistic support and help, giving comfort and giving pep-talks, negotiations with the government and the VAPH (Flemish Agency for People with a Handicap – FAPH). The latter ones have now changed in terms of quantity, quality and speed. It's thanks to the Liga that the Belgian ALS patients were put on the world map. The Liga is part of the International Alliance of MND.
And last of all the ALS Liga started to actively cooperate with the scientific world. Not just to gain information, but to encourage the researchers.
ALS was also put in the spotlight. Several published articles tripled during these 10 years which means the people now know the disease and the patients can talk about it more easily. This is important because the funds needed for scientific research have to come from the government and the industry and this can only happen when these last two are interested. The ALS Liga gets the honor of being the one to put the disease ALS on all the agendas.
Professor Robberecht gives his thanks in name of the entire ALS team from Leuven to the Liga for their constructive and positive cooperation. But the ALS patients are thanked as well for their commitment in sometimes difficult clinical studies. The members of the board of the Liga are thanked as well for all the efforts they delivered and especially the chairman, who had an important and responsible job. Because the Liga is the best that can happen to patients, researchers and doctors, this initiative has to keep growing.
Again, thank you to Mister Reviers and his wife for organizing this afternoon.
Translation: Sara De Roy
