Mesenchymal stem cell-derived neural progenitors in progressive MS: Two-year follow-up of a phase I study

Abstract

Objective: To determine the long-term safety and efficacy of repeated intrathecal (IT) administration of autologous mesenchymal stem cell-derived neural progenitors (MSC-NPs) in patients with progressive MS by evaluating subjects 2 years after treatment.

Methods: Twenty subjects were enrolled as part of a phase I, open-label single-arm study of 3 IT injections of MSC-NPs spaced 3 months apart. Subjects were evaluated for adverse events and disability outcomes including the Expanded Disability Status Scale (EDSS) and the timed 25-foot walk (T25FW). Long-term evaluation was conducted 2 years after the third treatment. CSF was collected before and 3 months after treatment.

Results: Eighteen of the 20 study participants completed the full 2-year follow-up protocol. There were no long-term adverse events associated with repeated IT-MSC-NP treatment. Seven subjects showed sustained improvement in EDSS after 2 years, although the degree of improvement was not maintained in 5 of the subjects. Three of the 10 ambulatory subjects showed sustained improvement in the T25FW after 2 years. CSF biomarker analysis revealed a decrease in C-C motif chemokine ligand 2 (CCL2) and an increase in interleukin 8, hepatocyte growth factor, and C-X-C motif chemokine ligand 12 (CXCL12) after treatment.

Conclusions: Safety and efficacy of repeated IT-MSC-NP treatment was sustained for 2 years; however, the degree of disability reversal was not sustained in a subset of patients. CSF biomarkers altered in response to IT-MSC-NP treatment may reflect specific immunoregulatory and trophic mechanisms of therapeutic response in MS.

Classification of evidence: This study provides Class IV evidence that for patients with progressive MS, IT administration of MSC-NPs is safe and effective. The study is rated Class IV because of the absence of a non-IT-MSC-NP-treated control group.

Clinicaltrialsgov identifier: NCT01933802.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Schematic of phase I trial design testing 3 IT injections of autologous MSC-NPs

IT = intrathecal; MSC-NP = mesenchymal stem cell-derived neural progenitor.

Figure 2. Changes in EDSS scores up to 2 years after IT-MSC-NP treatment

(A) EDSS scores of 2 study subjects with sustained improvement of 2.0 or greater. (B) EDSS scores of 5 study subjects with sustained improvement of 0.5 points. (C) EDSS scores of 6 study subjects with stable disease throughout the course of the study. (D) EDSS scores of 5 subjects who showed disease worsening between baseline and long-term follow-up. Arrows in each graph represent each IT-MSC-NP treatment. EDSS = Expanded Disability Status Scale; IT = intrathecal; MSC-NP = mesenchymal stem cell-derived neural progenitor.

Figure 3. Decreased CCL2 and increased TGF-β2 in CSF following IT-MSC-NP treatment

Individual values at baseline and post-treatment for all study subjects are shown. Levels of (A) CCL2 were significantly decreased and (B) TGF-β2 significantly decreased in CSF sampled 3 months after the third IT-MSC-NP treatment compared with baseline. (C) CSF levels of CCL2 and TGF-β2 were inversely correlated. IT = intrathecal; MSC-NP = mesenchymal stem cell-derived neural progenitor; TGF = transforming growth factor.

Figure 4. Increased inflammatory biomarkers in CSF of subjects who lacked EDSS improvement following IT-MSC-NP treatment

Individual values at baseline and post-treatment for subjects who showed improved EDSS (black lines) and subjects who lacked EDSS improvement (gray lines) are shown separately in left and right panels, respectively. Levels of (A) HGF, (B) CXCL12, and (C) IL-8 were significantly increased post-treatment in the CSF from nonresponders compared with responders. (D) Overall levels of CSF NfL were not significantly altered post-treatment in either group. In subjects with elevated CSF NfL (>1,000 pg/mL), responders exhibited decreased CSF NfL, wherease nonresponders exhibited increased CSF NfL after treatment. EDSS = Expanded Disability Status Scale; HGF = hepatocyte growth factor; IT = intrathecal; MSC-NP = mesenchymal stem cell-derived neural progenitor; NfL = neurofilament light.