Reply to “New Horizons for Multiple Sclerosis Therapy: 2025 and Beyond”

We thank Dr. Birnbaum for his thoughtful comments on our recent review. We chose to focus our review on aspects of multiple sclerosis (MS) pathology that we felt were most likely to represent actionable therapeutic targets in the near future. We agree with Dr. Birnbaum that inherent abnormalities in the central nervous system (CNS) of patients with MS could exacerbate, modify, or even initiate autoimmune CNS demyelination, consistent with the “inside-out” model of MS.1 Additional systemic factors, such as alterations in the gut microbiome2 and metabolic dysfunction,3 are also potentially important contributors. A key need for the field is to determine the causative roles of such processes as well as more detailed mechanisms, to advance development of more effective therapeutics. Comprehensive therapies aimed at all causes of both CNS injury and repair will hopefully enable the complete cure for MS that we all seek. Joseph J. Sabatino Jr.: Writing – review and editing; writing – original draft. Bruce A. C. Cree: Writing – review and editing. Stephen L. Hauser: Writing – review and editing.