Remyelination trial failures: Repercussions of ignoring neurorehabilitation and exercise in repair

Abstract

Several putative neurorestorative therapies in multiple sclerosis (MS) have recently failed; this includes high-dose biotin, bexarotene, a retinoic acid receptor gamma agonist, and opicinumab (anti-LINGO-1). Are these failures biological or due to poor trial design? We argue that the failure to include exercise in these trials and selecting participants without the capacity for repair may explain these disappointing results. We propose the need for mapping the biological mechanisms of recovery within trials, understanding the critical window when remyelination/repair occurs in terms of targeting interventions at the right time and selecting subjects who are capable of repair. We also make the case for testing combinations that include other pro-repair interventions such as exercise, Nrf2 inducers and possibly neurostimulation. The MS community can't afford for any more treatments to fail because of poor trial design and ignoring biology.