Project Portugal 2030

Summary

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of both upper and lower motor neurons. Currently, only a limited number of drugs, approved by regulatory agencies such as the FDA (seven) or EMA (one), offer marginal relief in slowing the functional decline of ALS patients, with no definitive cure available. Given the average life expectancy of merely two to five years post-diagnosis, there is an urgent necessity for biomarkers to enhance patient care and accelerate ALS treatment advancements. This innovative project seeks to establish a platform for discovering biomarkers, primarily utilizing mid-infrared spectroscopy technology (MIR). Identification of fluid biomarkers for diagnosis, prognosis, susceptibility, and treatment response in ALS is a critical goal. This is pivotal for expediting and refining the diagnosis, predicting prognosis, optimizing clinical trial designs, and interpreting trial outcomes. MIR stands out as a rapid, accurate, and highly reproducible tool for simultaneous analysis of multiple components, requiring only a small sample volume (typically a few microliters) without complex preparation, thereby preserving sample integrity. Emphasizing patient well-being, the project will make use of less invasive samples like saliva, urine, and blood. In order to validate potential ALS biomarkers identified by MIR, and leveraging the team's expertise in metabolism and mitochondrial dysfunction, urine-derived stem cells and peripheral blood mononuclear cells will be obtained from ALS patients and matching controls. Additionally, a longitudinal study, collecting samples every four months, is planned to identify prognostic biomarkers. Due to the clinical and pathophysiological heterogeneity of ALS, diagnostic biomarkers could potentially stratify patients, unveiling distinct ALS subtypes. ALS, like other neurodegenerative disorders, may initiate months or years before symptom development. Thus, identifying biomarkers that detect these processes during the presymptomatic stage could provide a means to monitor impending disease onset [in the case of familial ALS (fALS)] or susceptibility/risk biomarkers to predict [sporadic ALS (sALS)] onset, allowing for preventive measures to slow or avert disease onset. In addition, prognostic biomarkers forecasting disease severity and progression would be invaluable for ALS patients. From a clinical standpoint, reliable prognostic biomarkers would assist in care plan development, paving the way for precision medicine. For clinical trials, such biomarkers would enable the stratification of patients based on variations in disease severity and progression, ensuring treatment groups include individuals expected to progress at different rates. Predictive biomarkers would enrich study populations, selecting individuals more likely to benefit from treatment, preventing the masking of drug efficacy due to non-response from those unlikely to benefit from the drug. As biomarkers possess the potential to bring about positive transformations in ALS patient care and treatment development, it is imperative to channel substantial efforts into the exploration and discovery of these biomarkers. This will benefit from the increase in the advance in knowledge of ALS pathomechanisms, application of new advanced technologies and bioinformatics.