ALS is a terrible disease, but scientific research into diagnosis and treatment may improve outcomes. The ALS center is currently running a large number of clinical trials ranging from gene therapy to drug repurposing. Prof. dr. Dr. LH (Leonard) van den Berg and Dr. MA (Michael) van Es say that all this research is aimed at finding new medicines for these seriously and progressively ill people.
People can go to the ALS outpatient clinic of the UMC Utrecht within two weeks for a second opinion or for a referral. “For example, because the referrer wants to know for sure whether the diagnosis of ALS, after all a death sentence, is correct,” says Van den Berg.
Diagnostics
The diagnosis in the ALS center takes place on the same day as the initial intake. The people come in the morning and in about 90% there is a probability diagnosis at the end of the day. The possibility of DNA diagnostics is also discussed. “Everyone who works in the outpatient department has a lot of experience with ALS and diseases that resemble it,” adds Van Es. “Nowadays we get 700 referrals a year. That number has increased enormously, so there is a great need for this concept.”
A point of attention in the diagnosis is that ALS can coexist with frontotemporal dementia (FTD). “We conduct specific studies to record this,” Van Es says. “The focus is often very much on muscle weakness, but we don’t always realize that behavioral and cognitive changes can also be part of the disease. The treatment teams attach great value to the neuropsychological evaluation, because it allows them to better respond to the needs of the patient and their relatives and also better estimate which therapies will be effective.”
After the diagnosis, the patients go for further care to one of the approximately 30 multidisciplinary treatment centers in the Netherlands, which meet the criteria for optimal care for these patients.
Genetics and Gene Therapy
10%, possibly slightly more, of ALS is familial and an abnormality in a gene is increasingly found in this group. Van den Berg estimates that 10 years ago the genetic abnormality could be detected in only 30%; today this is possible in 70-80% of familial patients. A DNA abnormality is also found in 10% of patients without a clear family history. The improved DNA diagnostics is thanks to very large genetic studies, such as Project Mine (www.projectmine.com), in which the DNA of (tens) thousands of people has been mapped. This project was set up by the ALS center and is coordinated from Utrecht.
One of the discoveries is that there is not just one form of familial ALS; more than 30 genes are involved. “ALS is probably not one disease, but a group of several diseases, which may require different treatments,” says Van den Berg. “One of the themes within our research is to find out what those subgroups are and thus move more towards personalized or precision medicine.”
Gene therapy is currently emerging as a possible future treatment for ALS. Many studies are being done that are directly related to a certain genetic abnormality, for example in the C9orf72gene, which is the most common genetic abnormality in ALS, but in SOD1-, FUS– in ATXN2genes.
Various and many medication studies
Importantly, many people with ALS (want to) participate in clinical trials. In surveys, 60-70% indicate that they are interested. “When patients are referred to us, we always discuss ongoing studies and the possibility to participate in them,” Van den Berg says. Various medicines are evaluated from a European network of 36 ALS centers controlled from Utrecht – called TRICALS (www.tricals.org).
In addition to studies in collaboration with the pharmaceutical industry, the ALS center also conducts investigator-initiated research, often into drugs that are registered for another indication and whose patents have expired. “That is drug repurposing,” says Van Es. “For example, a drug has been proven effective against HIV, but we think that drug could also have a different mechanism of action that is useful for ALS. We also conduct similar research into lithium. In previous studies (including the Dutch LITRA study), the drug did not appear to be effective. Then we looked at that data again and divided the patients into subgroups, based on genetics. In addition, there appeared to be one genetic subgroup with an abnormality in the UNC13agene, which did benefit from lithium. Now we have started a new study, MAGNET, with lithium in just that genetic subgroup.”
There are also 4-5 studies underway for patients in whom no genetic abnormality has been found. “One study is underway into a combination of two drugs,” says Van den Berg† “In ALS, a combination therapy has been investigated in a phase II study. We are now in a phase III study. So studies are also being conducted with ALS patients without genetic abnormalities on different drugs with different mechanisms of action.”
Discuss trial participation!
In view of the large number of ongoing studies, it is important that the possibility of trial participation is discussed with every patient (people can register via [email protected]). In addition to these drug studies, the ALS center also conducts preclinical research into disease models using stem cells and organoids, as well as epidemiological studies and clinical research into neurophysiological biomarkers and imaging.