Development of a novel fluorescent tracer for detection of retinal TDP43 in ALS and FTD

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Project Summary Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) define two ends of a spectrum of clinically, genetically, and mechanistically related neurodegenerative diseases. Due to symptom overlaps with other diseases, the early and accurate diagnosis of ALS and FTD is challenging. This leads to delayed intervention and stands as a major barrier to the efficient clinical testing of new disease-modifying therapeutics. Efforts to develop new therapies and apply them early would be greatly facilitated by biomarkers that reveal the state of ALS/FTD pathogenesis in vivo at the molecular level. Currently there are no objective diagnostics to non-invasively detect and measure the most defining molecular feature of ALS/FTD pathogenesis: accumulation of deposits of the TAR DNA-binding protein 43 (TDP43). A buildup of TDP43 deposits occurs in ~97% of ALS and ~50% of FTD cases and is thought to be a central driver of disease pathogenesis. This proposal will generate proof of concept for an affordable, accessible and innovative approach to detect and quantify TDP43 pathology in ALS/FTD human eyes using patent protected small molecule fluorescent retinal contrast agents.