Abstract Amyotrophic Lateral Sclerosis (ALS) is a universally fatal neurodegenerative disease that afflicts over 1 out of every 10,000 individuals. Protein aggregation has been implicated as a primary driving force in ALS and multiple other neurodegenerative illnesses. TDP-43 is the principle component of the protein aggregates in ALS, and TDP-43 also stands out as the only genetically defined ALS mutant gene that is also the hallmark pathology of sporadic ALS. TDP-43 is a RNA binding protein that is nuclear under basal conditions but translocates to the cytoplasm during stress where it forms RNA/protein aggregate complexes termed "stress granules" (SGs). Disease-linked mutations in TDP-43 enhance the ability of TDP-43 to aggregate and form SGs in vitro and in animal models. Cytoplasmic TDP-43 aggregates accumulate and also co-localize with SGs in the spinal cord and brain of patients with ALS, as well as in cellular and animal models of ALS. These integrated observations all point to a strong biological connection between TDP-43 and pathogenesis of ALS. Aquinnah Pharmaceuticals licensed 10 lead compounds that inhibit TDP-43 and SG aggregation that were identified in a high throughput screen performed in the laboratory of Dr. Benjamin Wolozin (Boston University School of Medicine). In Phase I of SBIR funding, we demonstrated the feasibility of targeting TDP-43 with these lead compounds for the treatment of ALS. We identified two oral bioavailable lead compounds that exhibit superb potency, brain pharmacokinetics (penetration and half-life), and show improvement in TDP-43 pathologic biomarkers in vitro and in vivo using a transgenic mouse model of TDP-43 of ALS. This SBIR Phase II proposal presents a plan for the further preclinical development of a first-in-class, novel, small molecule oral drug for the treatment of patients with ALS, to slow and possibly reverse disease progression. Following success with our aims, we will advance to an Investigation New Drug (IND) application filing with the FDA and initiate Phase I clinical trials to provide promise to patients with ALS.

Project Narrative Amyotrophic Lateral Sclerosis (ALS) is a universally fatal disease for which there are currently no effective treatments, which means there is a dire need for novel therapeutic approaches in this field. This proposal aims to optimize new therapeutic compounds that prevent and reverse TDP-43 aggregates, which is the hallmark pathology found in >90% of patients in both sporadic and familial cases, and to develop a lead drug candidate that can be tested in the clinic.