Human umbilical cord mesenchymal stromal cells therapy for neuromyelitis optica spectrum disorder: a phase 1/2a trial

Current treatments for neuromyelitis optica spectrum disorder (NMOSD) highlight recurrence management, while little attention is paid to the relief of residual neurological dysfunction. Here we aimed to evaluate the safety and efficacy of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in reducing relapses and mitigating neurological impairments. This trial, hUC-MSC-NMOSD (ChiCTR-INR-16008037), a single-arm, dose-escalation, open-label study, included 31 NMOSD patients of three dose groups received four infusions every three months, with 15-month follow-up. Primary outcome was time to first recurrence; secondary outcomes focused on clinical scores, MRI lesions and exploratory findings. HUC-MSC infusion was well tolerated in all groups of patients. Adverse events were mostly mild, with urinary tract infections being the most common. Severe adverse events were rare and unrelated to the treatment. The median relapse-free interval increased significantly post-treatment from 305 (95%CI 226-382·5) to 760 (589-1016·5) (p < 0·001), especially in the medium- and high-dose groups. During the two years before and after therapy, the mean Annualized Relapse Rate (ARR) dropped considerably from 1 (0·75-1) to 0 (0-0·5) (p < 0·001). Clinical scores improved in the low and medium-dose groups. The total volume of high-signal white matter lesions in brain significantly decreased after therapy from 4144·5 (2857·2-5508·6) to 2914·4 (2453-3684·11) (p = 0·016). Exploratory single-cell RNA sequencing and metabolomics detection revealed a potential participation of thioredoxin and oxidative phosphorylation (OXPHOS)-mediated boosting of Treg differentiation and suppressive capacity. This trial indicates that intravenous hUC-MSC administration is safe and shows potential efficacy in treating NMOSD. Medium dose might be the best possible compromise between safety and effectiveness.