Amyotrophic lateral sclerosis (ALS) is a devastating disease for which there are still no accurate tools for diagnosis, disease monitoring or treatment. Several national and international initiatives are currently focused on establishing large-scale biobanks and repositories to collect clinical and molecular data from extensive ALS cohorts, with the aim of identifying novel associations and generating new hypotheses about disease progression. However, an emphasis on managing large-scale datasets without a unified framework to understand the origin and significance of the diverse clinical and molecular alterations observed across different forms of ALS substantially limits the discovery of truly disease-specific biomarkers and often leads to unreliable conclusions.
 
 
To address this challenge, we propose the establishment of a national consortium bringing together basic and clinical researchers to develop a validated, sustainable platform of molecular knowledge and tools for ALS. Rather than prioritising the inclusion of the largest possible number of cases or the validation of individual biomarkers, our strategy will focus on defining a finite set of longitudinal samples that captures the heterogeneity of the disease while providing sufficient statistical power to characterise the molecular changes underlying ALS progression.
 
 
Using this representative cohort, we will undertake a multidisciplinary characterisation of sample composition to generate a shared database following Good Laboratory Practice (GLP) standards. We will then integrate the clinical, epidemiological and biomarker data generated and validated from this longitudinal cohort to establish a prototype ALS progression curve, designed to become increasingly robust through the incorporation of data from additional repositories over time. In addition, the consortium will bring together our expertise in biomarker discovery and experimental validation using cellular and animal models within a single virtual platform to assess the impact of potential therapeutic compounds.
 
 
Our work plan is structured around specialised cores with clearly defined objectives and coordinated activities. By fostering a new collaborative framework between clinical and basic researchers, the consortium will advance our understanding of ALS while delivering tangible benefits for patients and public health authorities.
This study has been funded by Instituto de Salud Carlos III through the project "SEED-ALS: Esfuerzo sinérgico para desarrollar y acelerar el avance en la investigación en ELA (PMPER24/00017)" (Co-funded by European Regional Development Fund/European Social Fund; “A way to make Europe”/"Investing in your future").

 

ROLE OF CNAG

CNAG is part of the Epidemiology core. This core will be responsible of the generation of a genetic and epigenetic characterization of the previously selected group of longitudinal samples through a national collaboration with the genetics core. This core will integrate all data collected in our subset of samples for its bioinformatic and statistical modelling to produce mechanistic hypotheses and causal pathways rather than simple associations. This core will generate a genetic characterization of our 'model' cohort, utilizing existing infrastructure and data in collaboration with initiatives (e.g, Impact Genomica, Precision ALS). It will also integrate all collected data from our sample subset for bioinformatic and statistical modeling, producing mechanistic hypotheses, causal pathways, and a preliminary ALS progression curve. CNAG will perform sequencing.

 

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