PhenotYpe Research for ALS ModIfyer Discovery.

Amyotrophic lateral sclerosis is a relentlessly progressive neurodegenerative disorder of motor neurons, leading to death of the patient on average only 36 months after disease onset. ALS is characterized by heterogeneity at the clinical and genetic level. Causative mechanisms of motor neuron degeneration are studied in several European studies, in particular Euro-MOTOR. Notwithstanding these efforts, ALS causative mechanisms remain only partially understood and therapeutic strategies based on these mechanistic insights are largely ineffective. The only drug available- Riluzole- extends the lifespan of ALS by 6 months, presumably by targeting disease modifying rather than disease causing targets. Therefore, we hypothesize that targeting disease modifying factors is important to accelerate the development of novel, alternative therapeutics, that will complement the search for causative mechanisms and therapies already covered in other projects. In this project, using unbiased genetic, proteomic, epigenetic and gene-expression techniques, we aim to identify modifiers of disease progression. We want to exploit the phenotypic heterogeneity of patients by comparing ALS patients with very fast disease progression to patients with slow disease progression. Using this original study design we aim to identify the factors that protect a subset of patients from an aggressive disease. Data collection and sample management will be done according to harmonized European ALS sampling and data management standards developed through the EU funded project SOPHIA. In addition, the detailed prospective clinical monitoring of patients will allow us reliably delineate the parameters that predict fast disease progression already in patients early in the disease. Insight into disease modifying factors will enhance our understanding of motor neuron degeneration and reveal potential therapeutic strategies.

Focusing on disease-modifying rather than etiologic mechanisms may accelerate the development of novel therapies and complement current research initiatives on causative mechanisms and curative therapies.

Month 35.

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