[Emerging Therapeutic Strategies for Central Nervous System Regeneration]

Reperfusion therapy has markedly improved outcomes after acute ischemic stroke; however, many patients remain ineligible for treatment or sustain irreversible brain injury despite successful recanalization. Regenerative medicine therefore represents an important strategy for restoring damaged neural tissue and promoting functional recovery. Stem cell therapies may exert therapeutic effects through multiple mechanisms, including cell replacement, secretion of neurotrophic factors, modulation of inflammation and immune responses, angiogenesis, and intercellular transfer of mitochondria and other bioactive molecules. Several regenerative medical products have received conditional, time-limited approval in Japan for central nervous system (CNS) disorders, including traumatic spinal cord injury, traumatic brain injury, and Parkinson disease. However, no stem cell product has yet been approved for ischemic stroke. Recent randomized, placebo-controlled trials have evaluated several cell-based therapies. The TREASURE trial evaluating allogeneic multipotent adult progenitor cells and the J-REPAIR trial evaluating allogeneic dental pulp stem cells failed to meet their primary efficacy endpoints. In contrast, a phase 2 trial of CL2020, an allogeneic Muse cell-based product, demonstrated acceptable safety and promising signals of functional recovery in patients with subacute ischemic stroke. Further studies are required to optimize cell type, dose, timing, route of administration, and patient selection, and to establish efficacy in adequately powered clinical trials.