Functional Biomarkers for ALS

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Project Summary Functional non-invasive biomarkers are critical for therapeutic target engagement outcomes in progressive rare diseases. Amyotrophic lateral sclerosis (ALS) clinical trial development has an urgent need for functional biomarkers to assess therapeutic response and target engagement. We will fulfill that urgent need. We have a history using functional blood-based biomarkers for clinical trials in ALS. Rasagaline (a neuroprotective compound) showed mitochondrial biomarker target -engagement in an open-labeled trial. A subsequent multi-center placebo-controlled trial failed to replicate target engagement. Disparities among clinical trial outcomes revealed issues with sample handling and the need for a generalized estimating equation (GEE) statistical model. Without the ability to accurately detect target engagement therapeutic opportunities will be lost. ALS pathological features include mitochondrial dysfunction and loss of proteostasis (protein aggregation). Mitochondrial dysfunction and proteostasis are intricately linked biological modalities which are key targets for upcoming clinical trials in ALS. These clinical trials will benefit from our functional biomarkers. We will clinically validate blood based mitochondrial and proteostasis biomarker protocols for use as indices of target engagement in future clinical trials. We will compare mitochondrial and proteostasis biomarkers within ALS and control subjects over eight months. We will develop a GEE statistical model to provide guidance for power calculations in our future planned clinical trials. We will determine biomarker relationships and develop a predictive statistical approach for our novel functional biomarkers.