Efficacy of Intrathecal Mesenchymal Stem Cell-Neural Progenitor Therapy in Progressive MS: Results from a Phase II, Randomized, Placebo-Controlled Clinical Trial

Background: Mesenchymal stem cell-neural progenitors (MSC-NPs) are a bone marrow-derived population of cells with therapeutic potential in multiple sclerosis (MS) based on their trophic and immunomodulatory properties. The primary objective of this study was to determine efficacy of intrathecal (IT) MSC-NP treatment in patients with progressive MS. Methods: The study is a phase II randomized, double-blind, placebo-controlled clinical trial with a compassionate crossover design conducted at a single site. Subjects were stratified according to baseline Expanded Disability Status Scale (EDSS) (3·0-6·5) and disease subtype (secondary or primary progressive MS) and randomized into either treatment or placebo group to receive six IT injections of autologous MSC-NPs or saline every two months. The primary outcome was EDSS Plus, defined by improvement in EDSS, timed 25-foot walk (T25FW) or nine-hole peg test after one year in the per protocol population. Secondary outcomes included the six-minute walk test (6MWT). This trial is registered with Clinicaltrials.gov, NCT03355365. Findings: From August 10, 2018, to June 2, 2020, 54 subjects were randomized into MSC-NP (n=27) or saline (n=27) groups. There was no difference in EDSS Plus improvement between the MSC-NP (33%) and saline (37%) groups (p=0·666). In subjects who require assistance for ambulation (EDSS 6·0-6·5) there was a significantly higher percentage of improvement in T25FW and 6MWT in the MSC-NP group (3·7% ± 23·1% and -9·2% ± 18·2%) compared to the saline group (-54·4% ± 70·5% and -32·1% ± 30·0%), (p=0·030 and p=0·036, respectively). There were 76 adverse events in 38 of 54 subjects (70%) receiving MSC-NP injections compared to 42 events in 27 of 51 subjects (53%) during saline injections. Biomarker analysis demonstrated increased MMP9 and decreased CCL2 levels in the cerebrospinal fluid following treatment. Interpretation: These results suggest that IT-MSC-NP treatment may be associated with a therapeutic response in a subgroup of MS patients. Trial Registration: This trial is registered with Clinicaltrials.gov, NCT03355365. Funding: National Multiple Sclerosis Society, Biogen, The Damial Foundation. Declaration of Interest: VH and SS are listed as inventors on a US patent issued to the Tisch MS Research Center of New York and is considered a non-financial competing interest. All other authors declare no competing interests. Ethical Approval: The study was approved by Western Institutional Review Board. All patients gave written informed consent. An independent external data and safety monitoring board evaluated all safety data on a yearly basis.