PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice

Peroxisome-proliferator-activated receptor delta (PPARδ) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPARδ agonists, KD3010 and T3D-959, in two established ALS/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43^Q331K transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9-10 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43^Q331K mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement-particularly for T3D-959-neither PPARδ agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPARδ activation without therapeutic benefit. Together, these findings demonstrate that PPARδ agonism is insufficient to modify disease progression in these ALS/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.