Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis

Abstract

Objective: To assess the safety and efficacy of 2 repeated intrathecal injections of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in amyotrophic lateral sclerosis (ALS).

Methods: In a phase 2 randomized controlled trial (NCT01363401), 64 participants with ALS were randomly assigned treatments (1:1) of riluzole alone (control group, n = 31) or combined with 2 BM-MSC injections (MSC group, n = 33). Safety was assessed based on the occurrence of adverse events. The primary efficacy outcome was changes in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to 4 and 6 months postinjection. Post hoc analysis includes investigation of cerebrospinal fluid biomarkers and long-term survival analysis.

Results: Safety rating showed no groupwise difference with absence of serious treatment-related adverse events. Mean changes in ALSFRS-R scores from baseline to 4 and 6 months postinjection were reduced in the MSC group compared with the control group (4 months: 2.98, 95% confidence interval [CI] = 1.48-4.47, p < 0.001; 6 months: 3.38, 95% CI = 1.23-5.54, p = 0.003). The MSC group showed decreased proinflammatory and increased anti-inflammatory cytokines. In good responders, transforming growth factor β1 significantly showed inverse correlation with monocyte chemoattractant protein-1. There was no significant difference in long-term survival between groups.

Interpretation: Repeated intrathecal injections of BM-MSCs demonstrated a possible clinical benefit lasting at least 6 months, with safety, in ALS patients. A plausible action mechanism is that BM-MSCs mediate switching from pro- to anti-inflammatory conditions. A future randomized, double-blind, large-scale phase 3 clinical trial with additional BM-MSC treatments is required to evaluate long-term efficacy and safety. Ann Neurol 2018;84:361-373.

Figure 1

Study design and trial profile. (A) The study design. (B) Scheduling of screening, randomization, treatment, and follow‐up of the participants. The full analysis set was defined as all randomized participants with baseline data and at least 1 efficacy value. *Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score was assessed for the primary efficacy outcome. CSF = cerebrospinal fluid; MSC = mesenchymal stem cell; SAE = serious adverse event.

Figure 2

Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R) score in the full analysis set. (A) Changes from baseline in the mean ALSFRS‐R score change during the follow‐up period. (B) Adjusted mean ALSFRS‐R score during the 3‐month lead‐in and the 6‐month follow‐up period (piecewise linear mixed model over time). Data are given as least squares mean with standard error, and p value is for control group versus mesenchymal stem cell (MSC) group.

Figure 3

Changing patterns of cerebrospinal fluid (CSF) cytokine levels in the mesenchymal stem cell (MSC) treatment group. (A) Comparison of cytokine levels in CSF from patients before and after MSC treatment. Median and first and third quartiles (black bars) are shown, and each dot (black dot, before treatment; white dot, after treatment) represents individual data. Probability values were calculated using paired t test. Receiver operating characteristic analyses of individual cytokines compare before versus after MSC treatment in the test cohort. (B) Subgroup analysis in good responders and poor responders after MSC treatment. Correlation is shown between changes of transforming growth factor (TGF)‐β1 and monocyte chemoattractant protein (MCP)‐1 by MSC treatment in good responders at 4 and at 6 months; black lines indicate R ². After MSC treatment, participants with ≥50% improvement in Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised slope were defined as good responders and those with <50% improvement were defined as poor responders. *Statistically significant. TNF = tumor necrosis factor.