Recent Advancements in Drug Delivery Across the Blood-Brain Barrier in Amyotrophic Lateral Sclerosis (ALS).

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neurodegenerative disease with limited therapeutic options. The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) present major obstacles to central nervous system (CNS) drug delivery, restricting the effectiveness of many potential therapies. Increasing evidence suggests that BBB and BSCB dysfunction are not only barriers to treatment but also important contributors to ALS pathophysiology. OBJECTIVE: To examine current evidence regarding BBB and BSCB dysfunction in ALS and evaluate the implications of stage-dependent barrier alterations for CNS drug delivery and therapeutic outcomes. METHODS: Recent mechanistic, pathological, preclinical, and clinical studies examining BBB and BSCB alterations in ALS were reviewed. Evidence on tight junction disorganization, endothelial dysfunction, vascular leakage, altered transporter activity, and emerging therapeutic and drug delivery strategies was analyzed. RESULTS: Converging evidence indicates that BBB and BSCB dysfunction are intrinsic and progressive features of ALS pathophysiology rather than passive consequences of neurodegeneration. Barrier impairment emerges early in the disease course and evolves across clinical stages. Disruption of barrier integrity may increase motor neuron vulnerability while modulating CNS drug exposure. Emerging strategies that bypass, exploit, or restore barrier function hold promise for enhancing CNS bioavailability and improving therapeutic outcomes. CONCLUSIONS: Improved understanding of barrier alterations may facilitate development of more effective CNS-targeted therapies and improve therapeutic outcomes in ALS patients.