Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis

Abstract

ObjectiveTo 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).MethodsIn 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.ResultsSafety 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.InterpretationRepeated 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

Repeated intramuscular transplantations of hUCB-MSCs improves motor function and survival in the SOD1 G93A mice through activation of AMPK

“…In particular, in ALS, mesenchymal stem cells have also been used as therapeutic agents to ameliorate disease progression 20 . To date, many studies have shown that mesenchymal stem cells administered into the central nervous system, skeletal muscles or both exert positive effects on lifespan and motor function in disease models 5,7,21 . Although Intramuscular injections of hUCB-MSCs have no effect on survival of motor neurons in the spinal cord of SOD1 transgenic mice (Supplement Fig.…”

“…During ALS disease progression, the loss of neuromuscular junction and muscle atrophy are critically related to disease progression 4 . However, most studies have focused on the central nervous system, especially on the motor neurons, as the main targets to improve disease progression and survival [5][6][7] . As mentioned above, due to the dynamic communication of various cells involved in disease progression, such approaches that only focus on motor neuron death are not effective for developing therapeutic agents.…”

“…In particular, in recent clinical trials, intrathecal and intramuscular administration of human mesenchymal stem cells (hMSCs) in patients with ALS were found to be safe and to provide beneficial effects for patients, including up to 25% improvement in the slope of progression. Furthermore, another study showed that repeated intrathecal administration of MSCs showed a possible clinical effect for at least 6 months in ALS patients 7,[20][21][22][23] . Therefore, application of hMSCs could lead to the generation of beneficial effects for neurodegenerative diseases.…”

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

“…Although interventions with anti-inflammatory drugs in experimental neurodegenerative animal studies have not resulted in successful clinical trials, a more recent approach to treat such disorders, in both experimental animals and humans, with implanting bone marrowderived stromal cells (bm-SCs), seems very promising. Such transplants supposedly modulate the immune system in both acute (Deda et al 2008;Martinez et al 2017;Tsai et al 2018;Cofano et al 2019;Jin et al 2019) and chronic (Mazzini et al 2016;Ciervo et al 2017;Gashmardi et al 2017;Sykova et al 2017;Cizkova et al 2018;Garbuzova-Davis et al 2018;Oh et al 2018;Gugliandolo et al 2019) neurodegenerative disorders in experimental animals as well as in patients. Our own experiments with human bm-SC in experimental animal models of both an acute (traumatic spinal cord injury; tSCI) (de Munter et al 2019a;Romero-Ramirez et al 2020) and a chronic neurodegenerative disorder (amyotrophic lateral sclerosis; ALS) (de Munter et al 2019b) were fully in line with these findings.…”

Failure of intrathecal allogeneic mesenchymal stem cells to halt progressive demyelination in two boys with cerebral adrenoleukodystrophy

“…Ho et al reported on 33 patients who received two doses (1 × 10 6 cells/kg) of IT MSCs 1 month apart. Changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised score from baseline to 4 and 6 months after injection were significantly different from the non‐MSC‐treated group . There were also significant changes in CSF cytokines with increases in levels of transforming growth factor‐ beta 1 and decreases in monocyte chemoattractant protein‐1 in the treated individuals possibly indicating an anti‐inflammatory effect …”