Modify ALS (ModALS): Integration of OMICs and digital biology in mouse and human motor neuron models for fast-track therapeutic innovation – ModALS

Amyotrophic lateral sclerosis (ALS) is a fatal age-associated neurodegenerative disease, which affects predominantly motor neurons in the cerebral cortex and the spinal cord. Overall, a positive family history for ALS is documented in approximately 5-10% of all ALS patients. The monogenic causes for ALS discovered in recent years seem to be quite diverse at first glance. However, the physiological roles of the approximately 20 known ALS disease genes can be grouped according to few common functional denominators. One of the most prominent cell biological functions genetically linked to ALS is protein quality control, as several ALS disease genes cluster in the autophagy and/or ubiquitin-proteasome pathways.
Recently, several genes including TANK-binding kinase 1 (TBK1) and Kinesin Family Member 5A(KIF5A) have been described in the context of impaired proteostasis. Considering the relevance of dysregulated proteostasis mechanisms and impaired autophagy for ALS pathogenesis and other neurodegenerative diseases, we propose here a comprehensive characterization of preclinical ALS models based on human iPSC-derived motoneurons with mutations in TBK1 and KIF5A and analogous rodent models. Implementation of a multimodal strategy aligning quantitative and differential gene expression and structural and functional phenotyping data with AI-boosted data analysis pipelines will allow the development of a physiologically relevant, innovative and harmonized pre-clinical platform to advance the mechanistic understanding of ALS pathology and development of new pharmaceutical strategies. The developed platform will be implemented in a chemogenomic screening approach using selective small-molecule pharmacological agents as a proof of concept for the actionability of the platform and potentially generating novel entry points for the discovery of pharmacological modalities and drug repositioning strategies.