Ludo Van Den Bosch - From whole genome sequencing to therapeutic strategies in neurodegeneration
Channel: Institut des Hautes Études Scientifiques (IHÉS)
Date: 2018-03-27

The increasing number of patients suffering from neurodegenerative diseases in our aging Western society becomes a major burden to our social care system. There is currently no cure for any of these disorders. This lack of effective therapies is in a large part due to an insufficient understanding of  the  etiology  and  pathogenesis  of  neurodegenerative  disorders.  One  of  the  most  dramatic neurodegenerative disorders is amyotrophic lateral sclerosis (ALS). It is a fatal neurodegenerative disorder  primarily  affecting  the  motor  system.  The  disease  presents  with progressive  muscle weakness and median survival is limited to 36 months after the disease onset. No effective therapies exist. In about 10% of the patients, ALS is a familial disorder. Mutations in 4 different genes (C9orf72, SOD1, TARDBP and FUS) explain a large proportion of these, but the cause of the disease remains 
enigmatic  for  the  majority  of  patients.  Over  the  last  2 decades,  multiple  clinical  trials  had  only negative results, in part because our understanding of the disease mechanisms is insufficient to define clear therapeutic targets. Even in the light of an unknown disease cause, a better understanding of the molecular mechanisms that affect the severity of the disease would greatly advance the ALS field. A considerable degree of heterogeneity exists between patients in terms of both the age of 
onset and the disease progression rate. This suggest that important genetic modifiers exist. Modifiers of disease progression in ALS are candidate targetsfor therapeutic interventions. Within the Project MinE  consortium,  whole  genome  sequencing  (WGS)  is  already  performed  on  almost  5000  ALS patients and more than 2000 controls. 
This international collaborative effort is unprecedented and 
uses  the  state  of  the  art  technology  for  WGS.  The  analysis  of  modifiers  of  age  of  onset  and  of survival  of  the  whole  consortium  will  provide  information  on  genetic  modifiers. The  hits  are prioritized based on the likelihood of being detrimental on protein and regulatory level using various bio-informatical prediction tools. Subsequently, validation of these hits is performed in vitro and in vivo. In vitro models consist of different cell types derived from induced pluripotent cells (iPSCs) 
derived  from  ALS  patients.  In  vivo  models  range  from  Drosophila,  zebrafish  and  rodents.  By performing all these experiments, we will get a better understanding of the molecular mechanisms underlying the disease that could also be responsible for the wide range in age of disease onset and survival  after  disease  onset.  Altogether,  this  could  pave  the  way  for  the  development  of  novel therapeutic strategies to treat ALS.