iCell Motor Neurons, ALS TDP43, 01279

Tar DNA binding protein (TDP-43) is a highly conserved ribonuclear protein that accumulates as ubiquitinated inclusions in both Amyotrophic Lateral Sclerosis (ALS) and (Frontotemporal Dementia) FTD patients. TDP-43 normally shuttles between the nucleus and cytoplasm where it functions to regulate RNA splicing, stability and transport. TDP-43 neuropathology is found in most familial and sporadic ALS; therefore, understanding TDP-43 dysfunction may yield paths to therapeutic intervention.  Further TDP-43 mutations, including the M337V and Q331K variants, account for nearly 5% of familial ALS.  Therefore, understanding the pathogenic mechanism of these disease-causing mutations will increase our understanding of TDP-43 biology and identify disease-modifying treatments.

To facilitate ALS/FTD research efforts, isogenic models of ALS motor neurons were generated. CRISPR gene-editing was employed to introduce either the M337V or Q331K mutation into the parental induced pluripotent stem (iPS) cell line of our iCell Motor Neurons. These gene-edited iPS cells were fully differentiated into highly pure human cells that exhibit similar metrics to our apparently healthy iCell Motor Neurons.

Isogenic disease model iCell Motor Neurons ALS TDP43 M337V and TDP43 Q331K combined with iCell Motor Neurons provide a precision medicine-based approach that facilitates functional genomics studies, the identification of druggable pathways, and development of co-culture models to identify motor neuron phenotypes due to single base pair changes.  Together they can be used to identify altered function and disease mechanisms related to TDP-43, for drug discovery and identification of ALS/FTD therapeutic targets, and for development of neuromuscular junction disease modeling.