ALS: a disease with no cure yet that affects more than 4,000 patients
Amyotrophic lateral sclerosis (ALS) is the third most prevalent neurodegenerative disease in Spain. The ‘la Caixa’ Foundation, in collaboration with the Luzón Foundation, is promoting research that is leading us towards an improvement in the diagnosis and treatment of this disease, which currently has no cure. Just a few days before 21 June, World ALS Day, we take a look at some of these projects.
Amyotrophic lateral sclerosis, known as ALS, is a progressive and lethal neurodegenerative disease that affects motor neurons and causes symptoms of muscle weakness and atrophy, leading to immobility and death. Although there is currently no official registry, it is known that between 4,000 and 4,500 people suffer from it in Spain and, according to the Spanish Society of Neurology (SEN), 700 people develop the first symptoms every year. Although the life expectancy of patients is highly variable and depends on factors such as age, the speed of progression or the type of ALS (sporadic or familial), sufferers have an average life expectancy of between two and five years from diagnosis. However, advances in patient care and understanding of the determinants of disease progression are changing this picture: more than half of patients live more than three years and about 20% live five years or more.
The moment of diagnosis is devastating for the patient and family. "An announcement of a diagnosis of ALS is a life-changing blow that is hard to describe. It is a catastrophe. It is the sword of Damocles hanging over you. It is a death foretold. And it is difficult, first for the patient and then for those closest to them, to digest with a minimum of rationality what is happening to you, because you think it is not real and that is why it is so frustrating," explains María José Arregui, president of the Luzón Foundation, an organisation that works to raise awareness of this disease, improve the quality of life of patients and their families and promote research.
In this degenerative disease with a fatal prognosis, the neurons responsible for movement begin to die and muscle control is progressively lost. The clinical manifestations of ALS are highly variable. The most common onset symptoms are muscle weakness and decreased muscle mass in the limbs, and up to one third of patients first present with speech or swallowing difficulties. Over time, ALS progresses to muscle paralysis, leaving sufferers unable to move, speak or breathe.
Experts say that in most cases the origin of the disease cannot be determined: only 5-10% have a genetic component. Most likely, they say, there is no single aetiological factor, but a combination of factors leading to neurodegeneration in ALS. In 90% of patients, it is not known why the disease has developed, which helps to understand the complexity of the research being done to tackle ALS.
Commitment to research
Despite significant advances in the last decade, ALS research continues to require enormous efforts. Aware of this need, ‘la Caixa’ Foundation and the Luzón Foundation recently renewed the collaboration agreement that both entities have maintained since 2017 to strengthen the research fabric on this disease, with a focus aimed at seeking new treatments and improving diagnosis. "I believe that since that year there has been a before and after in terms of ALS research. We have managed to put the disease on the public and social agenda and make it attractive to researchers," says María José Arregui.
Since then, the CaixaResearch Call for Health Research has supported an ALS research project every year, in collaboration with the Luzón Foundation. One of them focuses on neuroinflammation, one of the pathogenic mechanisms that contribute to the onset and progression of ALS. Until now, anti-inflammatory drugs have proven ineffective in treating the symptoms and slowing its progression. Rubèn López Vales, from the Universitat Autònoma de Barcelona, is at the forefront of this first-ever research in this field. 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, in its pre-clinical phase, has successfully tested the efficacy of maresin in animal models by reducing inflammation and slowing disease progression, which has also opened up new hope for other neurodegenerative diseases such as multiple sclerosis.
"An analogy with chronic disease would be to look at a motorway full of cars that have collapsed as a result of an accident. Each of those cars would be an immune cell. What the anti-inflammatory drugs would try to do is to slow down or block the cars from entering the motorway to prevent further collapse and other cars from piling up on the motorway. However, until the accident car is removed, the cars are going to be held up. What are we doing with this therapy? We are the tow truck that is going to remove the damaged car and allow the cars that have been trapped to circulate," says the researcher.
Toxicity and pharmacokinetic studies are currently being carried out as a preliminary step to the start of a clinical study in patients. The aim is to transform these results into a treatment that slows down the progression of the disease.
© Pedro Sánchez. la Caixa’ Foundation
Liquid biopsy, a hope in ALS
Another of the lines of research into ALS, also within the framework of the collaboration between the ‘la Caixa’ Foundation and the Luzón Foundation, is the early diagnosis of the disease. At the Miguel Servet Foundation - Navarrabiomed, Maite Mendioroz Iriarte and Ivonne Jericó Pascual are leading a project in which a technique developed in the field of oncology is being used for ALS patients: 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. What we are doing is isolating and studying this DNA through blood analysis," explains Maite Mendioroz Iriarte, researcher and director of the Miguel Servet Foundation - Navarrabiomed. Her team is trying to identify new genes, which could be used as biomarkers for the diagnosis and progression of the disease. Moreover, this could also be applied to other neurodegenerative diseases such as Alzheimer's, Parkinson's or multiple sclerosis.
As the researcher points out, ‘our greatest hope is that the identification of these biomarkers will result in the development of a diagnostic test that allows greater precision and shortens detection times. This would undoubtedly reduce the burden of patient distress. We cannot forget that the average time to diagnosis of ALS is currently 10 months, a very long and distressing period of time for the patient and their environment.
But these are not the only projects currently being developed thanks to these institutions. In addition, the research led by Carmen María Fernández-Martos, which studies the neuroprotective role of leptin, a hormone related to the metabolism of obesity and which is associated with a lower risk of developing ALS, conferring a survival advantage on patients, stands out.
On the other hand, at the CSIC's Margarita Salas Biological Research Centre, Ana Martínez 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 the body's voluntary movement muscles. Their death is responsible for the functional paralysis that characterises ALS patients.
For his part, Óscar Fernández-Capetillo, from the CNIO, explores the role of nucleolar stress in ALS. To date, more than 22 genes with mutations in ALS patients have been identified. His group has discovered a new mechanism that links these mutations to a general problem that blocks all nucleic acids, DNA and RNA, and prevents a multitude of fundamental processes for the correct functioning of motor neurons.
The latest project to receive support from this collaboration is that of Estela Área, also from the CSIC's Margarita Salas Biological Research Centre. Previous studies by her team have shown that metabolic alterations in the motor neurons of these patients occur in the cytoplasm of the cell, in the endoplasmic reticulum. His research focuses on analysing and monitoring these alterations, both in animal models and in human cells and blood samples from ALS patients, to understand what role they play and thus open the door to finding new potential therapeutic targets.
The social reality for patients
In addition to increasing investment in ALS research, among other measures, the Luzón Foundation is calling on the government to provide adequate home care for ALS patients. "Care for ALS patients is deficient in our country and our health system is not prepared to care for them. Families often bear the full burden of care, sometimes at immense financial sacrifice, as the patient is sent home. Therefore, we believe it is vital that the new law ensures that patients receive quality care at home," says María José Arregui.
People suffering from ALS require multiple professionals in their daily care. Rehabilitative healthcare, such as physiotherapy, occupational therapy, psychological care, speech therapy or cognitive stimulation, is necessary to slow the progression of the disease and improve the quality of life of patients, who often suffer from anxiety disorders and depression. "The cost of the disease is unaffordable for patients and their families. We are talking about a disease that requires multidisciplinary treatment, which in most cases is assumed by the family, to which must be added that the main caregiver of the patient must sometimes stop working, with the consequent reduction in income," he laments.