Advances in ALS research 2021 by Talya Goble

Amyotrophic lateral sclerosis (ALS) is a disease of the nervous system, affecting nerve cells of the brain and spinal cord. These affected cells, called motor neurons, communicate signals from the brain to the muscles in our body and allow for voluntary movement. In ALS, death of these neurons results in progressive weakening and wasting of muscles leading to severe disability. Around 5000 people in the UK are living with ALS at any given time, however, it is still not entirely understood how and why certain individuals are affected.

Currently, Riluzole is the only drug that has been approved for the treatment of ALS in the UK. It acts by blocking a brain chemical called glutamate. Glutamate is responsible for passing messages from one nerve cell to another in the brain. However, motor neurons are particularly sensitive to glutamate and over-stimulation of them can be toxic. Therefore, Riluzole acts to protect against motor neuron death by blocking glutamate and slows the progression of the disease. However, there is still an unmet need for more treatments that can further slow, or even halt, progression of the disease as well as increase the quality of life for those living with ALS.

The vast majority of ALS cases are spontaneous (sporadic ALS) with estimates of only 5-10% of ALS patients inheriting the disorder from a parent (familial ALS). In these rare inherited cases, a few causative genes have been identified, including C9orf72 and SOD-1, and these genes have provided key insights into how the disease can start as well as progress. ALS researchers use a wide range of techniques and species to model the disease from fish to mice to human cells. Each model can provide a piece of the wider puzzle and lead to exciting new drug targets that can be tested in clinical trials.

Clinical trials are essential for finding new and effective treatments and are made up of three phases. The first phase assesses the drug for initial safety and usually involves a small group of healthy participants. The second phase will involve patients and test if the drug is effective as well as safe in those with the condition. If successful, the treatment will move onto the third phase which involves larger groups of patients who will be monitored for a longer period of time for signs of improvement or side effects. Once the treatment is deemed safe and effective by this strict and lengthy process, it can be approved for use. Currently, there are several promising clinical trials for ALS taking place in the UK:

  • Alexion CHAMPION-ALS: this clinical trial based in London and Sheffield is currently in its third phase of studying the new drug, Ravulizumab. Ravulizumab aims to help treat ALS by blocking a component of the immune system. Usually, our immune system is primed to kill foreign material, like bacteria or viruses, or even our own cells if they turn cancerous, but in ALS the immune system can incorrectly attack motor neurons and contribute to their death.  Previously, Ravulizumab has shown to increase survival in mouse models of ALS so announcement of the trial entering its third phase is very promising news.
  • TUDCA-ALS: is currently in its third phase and recruiting across the country. TUDCA stands for the drug it is trialling, taurousodeoxycholic acid, which was previously used to treat liver disease. TUDCA is being explored as an add-on to riluzole treatment and it has shown promise to protect against cell death by working as an antioxidant. Reactive oxygen species (ROS; also called free-radicals) are waste products produced by our cells when they turn the food we eat into vital, useful energy. However, if our cells produce too many ROS, or are less able to clear them up then they can get stressed and damaged. In cases of ALS where nerve cells are less healthy and already overwhelmed, antioxidants can help reduce this stress and protect against their death.
  • Biogen SOD1: is an almost decade-long study that started in 2016 to test the safety and effectiveness of a drug called Tofersen (also called BIIB067). This trial is aimed specifically for the 2% of ALS patients that have a mutation in a gene called SOD1. Each and every one of us have a unique genetic code that we inherited from our parents, our DNA. DNA provides thousands and thousands of recipes for the proteins that make us up, from our hair or eye colour to the enzymes that let us break down certain types of food. Some of the recipes, or genes, can come with mistakes meaning a protein is made that doesn’t work as it should. This is the case for the gene SOD1, where inherited mistakes cause this protein to become toxic, and this particularly affects motor neurons. Tofersen acts by reducing the amount of toxic SOD1 that is produced by the cells of SOD1-ALS patients therefore helping reduce the damage that it causes to motor neurons.
  • Biogen C9orf72 BIIB078: this trial is currently in its first phase, meaning it will be the first time the drug BIIB078 is tested in humans. Like the Biogen SOD1 trial, this trial is aimed at people with an inherited form of ALS, but specifically in those with a mutation in a gene called C9orf72. The C9orf72 gene provides the recipe for the C9orf72 protein which is present in many of our nerve cells and is important for how they communicate with one another.  However, in some people, the C9orf72 gene can be drastically bigger because a portion of the recipe is repeated hundreds of times. Here, this bigger gene can now make toxic products that kills the cells that it is expressed in. It’s estimated that mistakes in the C9orf72 gene are responsible for 40-50% of inherited ALS cases and is also linked with certain forms of dementia. The drug BII078 aims to reduce the number of toxic C9orf72 proteins that are produced, helping to protect them and increase their survival.

The last 18 months have taken a heavy toll on many people, communities and industries. Science research unfortunately has not been exempt from COVID-based obstacles. Nonetheless, many research groups adapted quickly allowing their vital work to continue by switching to online-based tools and home test-kits. Now, as the world begins to open up again, promising times lay ahead for ALS research with the anticipation of fundamental breakthroughs in the field. And with it, a new sense of hope for all those affected with this debilitating disease.