A PhD experience: Dr. Sergi Verdés

The doctoral thesis is a long journey full of unexpected twists; in fact, this project arises from a previous project that did not prosper and from the collaboration between two groups to join forces and find treatments for Amyotrophic Lateral Sclerosis (ALS).

ALS is a cruel and relentless disease that robs motor function as motor neurons die, leaving a trail of disability and suffering, ending with the death of patients within 2 to 5 years from diagnosis. Despite decades of research, we still do not have effective medications, and the mission to find treatment is more urgent than ever.

In this thesis, we focused on a promising molecule: Klotho. Have you heard of it? Known for its beneficial role in aging and longevity, Klotho exhibits surprising qualities, such as antioxidant, anti-inflammatory, and regenerative properties, suggesting a therapeutic potential we could not ignore. Some of these mechanisms are altered in ALS, where the interaction of multiple pathological factors likely results in the selective death of motor neurons. But even so, most research studies and failed clinical trials have focused on only one or a few main disease mechanisms. This is where Klotho stands out, offering a more integrated approach, as it can simultaneously counteract several ALS alterations.

At first, we discovered that Klotho levels decrease in nervous and muscle tissues in animal models of ALS. What does this mean? It could indicate a possible connection with disease progression. Initial experiments in spinal cord cultures revealed that increasing Klotho levels offered tangible hope. Klotho protected the delicate motor neurons from excitotoxicity, a process that contributes to their degeneration. With this knowledge, the next step was to treat mice with ALS to verify its therapeutic role. Imagine introducing the Klotho gene into these mice and exponentially increasing its levels. Impressive, right? Well, we achieved this in the spinal cord and muscles of these mice using gene therapy techniques.

The real breakthrough came when we turned our attention to the muscles. By increasing Klotho secretion in this tissue, we managed to preserve the contact with motor neurons, reducing their degeneration and muscle disconnection, decreasing inflammation, and maintaining muscle function in ALS. This intervention not only delayed disease onset and improved motor function but also extended the lifespan of the affected mice.

But we did not stop there. We wanted to uncover the molecular mysteries behind these effects. We conducted large-scale analyses to identify the main genes, proteins, and metabolic pathways through which Klotho exerts its protective effects. Some of these properties were already known, such as its antioxidant and anti-inflammatory roles, but we found new ones, like its involvement in protein metabolism or intracellular transport. These studies have offered us new perspectives on possible therapeutic strategies and their application in other neurodegenerative diseases.

But that's not all! New projects have emerged from this thesis to continue demonstrating Klotho's effectiveness in other ALS subtypes and injuries with neuromuscular implications, such as spinal cord or nerve injuries. Our work does not end here, as we recognize the importance of bringing these discoveries from the laboratory to the clinic. To facilitate this translation, we have patented this treatment and established contacts with pharmaceutical companies to promote the potential applications of our strategy.

In short, our findings not only offer hope for those affected by the disease but also highlight the importance of collaborative and team research in the quest for effective treatments. What do you think of this advancement? Do you believe we can make a difference in the fight against ALS? We are convinced!