Opinion: more mouse models and more translation needed for ALS

Amyotrophic lateral sclerosis is a complex disorder most of which is 'sporadic' of unknown origin but approximately 10% is familial, arising from single mutations in any of more than 30 genes. Thus, there are more than 30 familial ALS subtypes, with different, often unknown, molecular pathologies leading to a complex constellation of clinical phenotypes. We have mouse models for many genetic forms of the disorder, but these do not, on their own, necessarily show us the key pathological pathways at work in human patients. To date, we have no models for the 90% of ALS that is 'sporadic'. Potential therapies have been developed mainly using a limited set of mouse models, and through lack of alternatives, in the past these have been tested on patients regardless of aetiology. Cancer researchers have undertaken therapy development with similar challenges; they have responded by producing complex mouse models that have transformed understanding of pathological processes, and they have implemented patient stratification in multi-centre trials, leading to the effective translation of basic research findings to the clinic. ALS researchers have successfully adopted this combined approach, and now to increase our understanding of key disease pathologies, and our rate of progress for moving from mouse models to mechanism to ALS therapies we need more, innovative, complex mouse models to address specific questions.

Automated summary

Amyotrophic lateral sclerosis (ALS) is a complex disorder with mostly unknown cause, but around 10% of cases are familial and caused by mutations in over 30 different genes. Mouse models exist for many genetic forms of ALS, but there is currently no model for the majority of ALS cases that are sporadic. The development of potential therapies has primarily relied on limited mouse models and has been tested on patients with different etiologies. The use of complex mouse models and patient stratification in clinical trials has proven successful in cancer research, and adopting a similar approach could lead to better understanding of ALS pathologies and faster translation of research findings into effective therapies.