Intrathecal Therapies for Neurodegenerative Diseases: A Review of Current Approaches and the Urgent Need for Advanced Delivery Systems.

Neurodegenerative diseases (NDDs) pose an immense global health burden, and developing effective treatments is hindered by the blood-brain barrier (BBB). Intrathecal (IT) administration of therapeutics directly into the cerebrospinal fluid (CSF) bypasses the BBB, offering a promising avenue for antisense oligonucleotides (ASOs), gene therapies, antibodies, and stem cells for these disorders. This review synthesizes the current landscape of IT therapies for Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis based on the current literature and ClinicalTrials.gov. We highlight key trials and approaches, including the success of ASOs in spinal muscular atrophy and recent progress in other NDDs. However, the efficacy of these novel treatments is often constrained by the limitations of first-generation IT delivery systems, which struggle with uneven distribution, systemic leakage, and the demands of modern biologics. Drawing from recent analyses, we underscore the critical shortcomings of current devices and point out the innovations needed in shaping next-generation systems: subcutaneous access ports, CSF flow platforms, AI-driven adaptive dosing, nanoporous membranes, intrathecal pseudodelivery, and hydrogel scaffolds. We conclude by emphasizing the urgent need for these advanced IT drug delivery systems, alongside rigorous comparative assessments, cost-benefit analyses, and clear regulatory pathways to fully realize the potential of emerging CNS therapies and transform NDD management.