Blood-based Biomarker for Characterizing Progression and Therapeutic Response in Amyotrophic Lateral Sclerosis

In this Direct-to-Phase II SBIR application, NeuroDex, Inc. proposes to advance the development of a new blood-based biomarker TDP43, which is a potential marker of pathological progression in amyotrophic lateral sclerosis (ALS) and a biomarker of interest for frontotemporal dementia (FTD), Alzheimer’s disease (AD), and related dementias (ADRD). With support from the Congressionally Directed Medical Research Programs, TargetALS, and ALS Finding a Cure®, NeuroDex conducted biomarker discovery work that indicated TDP43 associated with neuron-derived extracellular vesicles (NDEs) in patient plasma has strong potential as a possible ALS diagnostic marker, a trial stratification tool, and/or an indicator of treatment response. Further development and commercialization of an assay for NDE-associated TDP43 is expected to improve the efficiency and success of clinical trials and to improve patient care and end-of-life planning. TDP43 has been proposed as a biomarker for ALS trials, but the ubiquity of TDP43 in tissues other than neurons has made it impossible to distinguish neuronal TDP43 from other sources in blood. NeuroDex previously developed an innovative technology (ExoSORT™) to selectively isolate NDEs from blood and examine their contents. In biomarker discovery work, NeuroDex evaluated the utility of NDE-associated TDP43 as a biomarker of changes in TDP43 in the brain, finding that NDE-associated TDP43 from blood 1) is significantly increased in a mouse model of the disease, suggesting it is an indicator of disease pathology; 2) is correlated with changes in ALSFRS-R scores over time, potentially providing a method for predicting rate of progression; 3) is correlated with levels of TDP43- regulated mRNAs; and 4) provides 96% sensitivity and 83% specificity for detecting ALS in combination with NDE-associated LC3 and Cathepsin D, indicating the potential for developing a combination of biomarkers to improve ALS diagnosis. Building on the success of the biomarker discovery phase, NeuroDex now proposes full analytical validation of the NDE-associated TDP43 assay and an initial characterization of the biomarker’s performance in stratifying patients to support a future clinical validation study. Aim 1. Validate analytical methods for ExoSORT in combination with the NDE-associated TDP43 assay. Success Metric: Assay performance meets or exceeds all FDA guidelines for validating bioanalytical methods. Aim 2. Characterize the ability of NDE- associated biomarkers to distinguish between slow and fast progressors with ALS through a longitudinal cohort analysis. Success Metric: ≥ 85% sensitivity and ≥ 75% specificity for distinguishing between slow and fast progressors. Impact—This project is expected to deliver a fully validated assay for NDE-associated TDP43 that can be adopted for patient stratification in ALS, FTD, AD, and ADRD clinical trials. The assay is also expected to have utility for tracking treatment response and improving diagnosis in clinical trials and clinical care. These applications would improve clinical trial efficiency and probability of success, leading to new treatments.