Colchicine as a Repurposed NLRP3 Inflammasome Inhibitor in Amyotrophic Lateral Sclerosis: Mechanistic Rationale, Existing Clinical Evidence, and Proposal for a Precision Biomarker Trial
Abstract
Background: : Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive motor neuron loss and neuroinflammmation. Current disease-modifying therapies provide only marginal benefit, and microglial NLRP3 inflammasome hyperactivation has emerged as a key pathological amplifier common to all ALS genetic and sporadic subtypes. Colchicine, an anti-inflammatory alkaloid approved for gout and pericarditis, potently inhibits NLRP3 assembly through tubulin disruption and direct blockade of ASC oligomerisation. Hypothesis and Aims: We hypothesise that low-dose colchicine can attenuate microglial NLRP3-driven neuroinflammation in ALS, thereby slowing motor neuron loss and disease progression. We present a mechanistic synthesis of the NLRP3 pathway in ALS, review available clinical and preclinical evidence for colchicine in neuroinflammatory diseases, and propose a precision biomarker-stratified clinical trial design. Methods and Evidence: We performed a systematic review of published literature on NLRP3 inflammasome activation in ALS, colchicine's pharmacology and safety profile, and relevant clinical trial evidence including the Co-ALS randomised controlled trial. Candidate biomarkers for patient stratification and outcome monitoring were identified from the literature.
Results:: NLRP3 inflammasome activation is documented across ALS subtypes including SOD1, C9orf72, and TDP-43 proteinopathies. Colchicine inhibits NLRP3 at multiple points,…
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