Table 1 Questions for translation from ALS mouse models to the clinic

• What are the disparate primary causes and pathogenic processes that lead to the similar clinical and cellular outcomes of sporadic and familial subtypes of ALS?

• Can we translate treatments for heterogeneous forms of ALS, without knowing specific molecular mechanisms?

• Can we create models for sporadic ALS?

• Have we missed drugs that would have been successful in people with SOD1-ALS?

• Are any treatments developed in SOD1 transgenics, other than ASOs for SOD1 itself, likely to work in the 98% of patients who do not have SOD1-ALS?

• How do we resolve the tension between the biology/pathology of ALS models versus the constraints of time/financial realities in pharma/biotech/academia?

• Can we create complex mouse models that give us disease progression/biomarkers/pathologies that are helpful for translation for each ALS subtype? How are these paid for?

• What markers of disease progression (biomarkers/endophenotypes), not of endstage, should we use in mouse preclinical studies to give us granular longitudinal data on drug effects prior to translation into humans?

• What markers of disease progression (biomarkers/endophenotypes) should we use in human clinical trials?

• How do we overcome the difficulties of patient heterogeneity and small numbers for each subtype, and trial stratification in translation from genetic mouse models to human ALS patients with sporadic and familial disease?