ALS: researching a disease still without a cure 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 Fundación Luzón, is promoting research aimed at improving the diagnosis and treatment of this disease, for which there is currently 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 fatal neurodegenerative disease that affects motor neurons, causing symptoms of muscle weakness and atrophy until the person becomes immobile and dies. Although there is currently no official register, it is known to affect between 4,000 and 4,500 people in Spain and, according to the Spanish Neurological Society (SEN), 700 people develop the first symptoms each year. While the life expectancy of patients varies greatly and depends on factors such as age, the rate of progression or the type of ALS (sporadic or familial), the average life expectancy is 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 both patient and family. “The announcement of an ALS diagnosis is a life-changing blow that is difficult to describe. It’s a catastrophe. It’s the sword of Damocles hanging over your head. It’s a death sentence. And it’s difficult, first for the patient and then for those closest to them, to digest with a minimum of rationality what’s happening to you, because you think it’s not real and that’s why it’s so frustrating,” explains María José Arregui, president of the Fundación Luzón, 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 seek medical advice due to difficulties with speaking or swallowing. 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 rather a combination of factors that lead to neurodegeneration in ALS. In 90% of patients, it is not known why the disease has developed, a fact that helps to understand the complexity of the research being conducted to combat ALS.

Commitment to research

Despite significant advances over the last decade, ALS research continues to require enormous efforts. Aware of this need, the ”la Caixa” Foundation and the Fundación Luzón recently renewed the collaboration agreement they have maintained since 2017 to strengthen the research fabric of 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’ve managed to place the disease on the public and social agenda and make it attractive to researchers,” says María José Arregui.

Since then, the CaixaResearch Health Call, in collaboration with the Fundación Luzón, has supported an ALS research project each year. One of these 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 progression of the disease. Rubèn López Vales, from the Universitat Autònoma de Barcelona, is at the forefront of the first-ever research in this field. He and his team have demonstrated that oral administration of a lipid derived from omega-3 fatty acids, maresin, has a greater therapeutic effect than riluzole, the only drug approved for ALS in Europe. The project, in its preclinical stage, has successfully tested the efficacy of maresin in animal models by reducing inflammation and slowing the progression of the disease, raising hopes for other neurodegenerative diseases such as multiple sclerosis.

“An analogy with this chronic disease would be to look at a motorway full of cars in a traffic jam due to 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 accumulating on the motorway. However, until the car in the accident is removed, the other cars are going to be held up. What are we doing with this therapy? We’re the tow truck that’s going to remove the damaged car and allow the cars that have been trapped to flow freely,” explains this researcher.

Toxicity and pharmacokinetic studies are currently underway as a preliminary step to starting a clinical study in patients. The aim is to translate these results into a treatment that slows the progression of the disease.

Liquid biopsy, a hope for ALS

Another line of research into ALS, also within the framework of the collaboration between the ”la Caixa” Foundation and the Fundación Luzón, is the early diagnosis of the disease. At the Miguel Servet Foundation - Navarrabiomed, Maite Mendioroz Iriarte and Ivonne Jericó Pascual are leading a project that applies a technique developed in oncology to 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, in this case the diseased neurons. What we’re 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 that could be used as biomarkers for the diagnosis and progression of the disease. Moreover, it could also be applied to other neurodegenerative diseases such as Alzheimer's, Parkinson's and multiple sclerosis.

As the researcher points out, “Our greatest hope is that the identification of these biomarkers will lead to the development of a diagnostic test that allows for greater accuracy and shorter detection times. This would undoubtedly reduce the burden on patients. We should not forget that the average time for diagnosis of ALS is currently 10 months, a very long and distressing period for patients and those around them.”

But these are not the only projects being developed thanks to these institutions. Another notable example is the research led by Carmen María Fernández-Martos, who is studying the neuroprotective role of leptin, a hormone linked to the metabolism of obesity and associated with a lower risk of developing ALS, which gives patients a survival advantage.

And at the CSIC's Margarita Salas Center for Biological Research, Ana Martínez and her team are developing a new compound that restores the functionality of the TDP-43 protein which is altered in ALS patients. The project has tested the efficacy of this compound in animal models because it prevents the death of motor neurons, the nerve cells responsible for producing the stimuli that contract the muscles involved in voluntary movement. Their death is responsible for the functional paralysis that characterises ALS patients.

For his part, CNIO's Óscar Fernández-Capetillo is exploring the role of nucleolar stress in ALS. To date, more than 22 genes have been identified as having mutations in ALS patients. His group has discovered a new mechanism that links these mutations to a general problem that blocks all nucleic acids, DNA and RNA, and hinders a variety of processes essential for the proper 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 Center for Biological Research. 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. Her research focuses on analysing and monitoring these alterations, both in animal models and in human cells and blood samples from ALS patients, to elucidate what role they play and thus open the door to finding new potential therapeutic targets.

The social reality of patients

In addition to increasing investment in ALS research, among other measures, the Fundación Luzón is calling on the government to provide adequate home care for patients affected by the disease. “The care of ALS patients in our country is inadequate and our health system is not properly prepared to attend to them. Families usually bear the full burden of care, sometimes with immense financial sacrifice, because the patient is usually sent home. That’s why we believe it’s vital that the new law ensures that patients receive quality care at home,” says María José Arregui.

People with ALS need a range of professionals in their day-to-day care. Rehabilitative care, 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 and depression. “The cost of the disease is unaffordable for patients and their families. We’re talking about a disease that requires multidisciplinary care, which in most cases is borne by the family, not to mention the fact that the patient's primary caregiver sometimes has to give up work, with the consequent loss of income,” she laments.