The "la Caixa" Foundation and the Francisco Luzón Foundation renew their alliance to support ALS research

In the last decade, important advances have been made in the knowledge of the causes and mechanisms of this disease thanks to basic and therapeutic research. However, ALS remains a rare disease, incurable for the time being and of unknown cause, affecting approximately 200,000 people worldwide, 4,000 of them in Spain.

ALS causes a progressive loss of motor neurons, resulting in muscle weakness and atrophy, until the affected person becomes completely immobile. Life expectancy is variable: 80% of patients die within the first five years. It is therefore necessary to continue to provide resources for research into this disease. The five research projects supported under the first collaboration agreement are working to advance understanding of the causes of the neurodegeneration process in order to improve the diagnosis and treatment of the disease, and they are doing so from multiple perspectives.

Although the causes of this disease are still unknown, it is known that neuroinflammation is one of the pathogenic mechanisms that contribute to its onset and progression. So far, anti-inflammatory drugs have proven ineffective in treating the symptoms and slowing its progression. Of the projects supported so far, the first to finish has been that of Rubèn López Vales, from the Universitat Autònoma de Barcelona. He and his team have shown that oral administration of a lipid derived from omega-3 fatty acids, maresin, has greater therapeutic effects than riluzole, the only drug approved for ALS in Europe. The project has successfully tested the efficacy of maresin in animal models by reducing inflammation and slowing disease progression. Following this preclinical stage, toxicity and pharmacokinetic studies are now being carried out as a preliminary step to the start of a clinical study in patients, with the ultimate goal of transforming these results into a treatment that will reach people affected by ALS.

For her part, researcher Carmen María Fernández-Martos is leading a project at the CEU San Pablo University to study the neuroprotective role of leptin, a hormone related to obesity, which scientific evidence shows is associated with a lower risk of developing ALS, conferring a survival advantage on patients with the disease. The team has achieved a unique animal model to evaluate new therapeutic targets and to study the mechanisms related to leptin. The project is an example of multidisciplinary research at an international level, as the animal studies are being carried out in Spain and, later, in Australia, the last part of the study will be carried out and the data will be validated in patient samples. This last clinical and research part will provide the answer to the role of leptin in motor neurons.

At the Miguel Servet Foundation - Navarrabiomed, Maite Mendioroz and Ivonne Jericó are leading a project in which a technique recently developed in the field of oncology is being used for ALS patients: the so-called liquid biopsy. The technique is based on the fact that when cells degenerate and die, they release their contents, including genetic material (DNA), into the bloodstream. These circulating DNA molecules contain biochemical information about their cells of origin, which in this case are the diseased neurons. These molecules can be isolated and studied by blood analysis. The project is successfully using this technique to isolate these DNA fragments in ALS patients and identify new genes that could be used as biomarkers for diagnosis and disease progression.

On the other hand, Ana Martínez, from the CSIC's Margarita Salas Biological Research Centre, and her team are developing a new compound that recovers the functionality of the TDP-43 protein, which ALS patients have modified. The project has tested the efficacy of this compound in animal models because it prevents the death of motor neurons, which are the nerve cells responsible for producing the stimuli that contract muscles throughout the body. Their death is responsible for the functional paralysis that characterises ALS patients.

The latest project to receive support from this collaboration is that of Óscar Fernández-Capetillo, from the CNIO, which explores the role of nucleolar stress in ALS. To date, more than 22 genes with mutations in ALS patients have been identified. The first mutation found was in the SOD1 gene, which is responsible for producing an enzyme whose function is to protect against oxidative stress-mediated damage. This is why some of the treatments approved for the treatment of ALS are based on antioxidants, although to date the impact of these therapies on patients' life expectancy has been modest. Apart from SOD1, a significant fraction of the mutations found in ALS patients involve RNA biology. However, the mechanism by which these mutations trigger the disease and, more importantly, the development of therapies against them, are areas where progress has been limited. In this context, Fernández-Capetillo's group has discovered a mechanism related to the general accessibility of nucleic acids, which has allowed them to explore new therapies that limit the toxicity of these mutations both in vitro and in animal models. With the support of the "la Caixa" Foundation, the laboratory will continue to work on understanding how mutations in RNA-related genes lead to ALS, and to try to exploit this knowledge to develop new treatments.