A phase II clinical trial with repeated intrathecal injections of autologous mesenchymal stem cells in patients with amyotrophic lateral sclerosis

Abstract

Background: Mesenchymal stem cells (MSC) were shown to induce beneficial effects in animal models of neurodegeneration and in pilot human trials in multiple sclerosis and amyotrophic lateral sclerosis (ALS). Aim: An open-label, clinical trial to evaluate the safety and efficacy of repeated intrathecal administrations of autologous-MSC in ALS-patients. Methods: The study included 20 subjects (age: 20–70) with definite diagnosis of ALS and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) score of >20. The patients were treated with 1–4 intrathecal injections of MSC, at intervals of 3–6 months. The primary endpoints were safety and tolerability. Efficacy measurements including ALSFRS-R score and forced vital capacity (FVC), were assessed as secondary endpoints. Results: No serious adverse events were observed during the whole period of the trial. One patient withdrew from the study before the first injection. The monthly rate of progression in ALSFRS-R was ameliorated by more than 25% in 15/19 patients between the 1st and 2nd injection (mean improvement of 107.1%); in 11/12 between the 2nd and 3rd injection and in 8/10 between the 3rd and 4th injection. Overall, during the whole period till the last transplantation 13 patients had a >25% improvement in the slope of progression of ALSFRS-R (mean improvement of 47.4%, p < 0.0038, Wilcoxon rank signed test). 7 out of 19 patients actually improved clinically (range of increase in ALSFRS-R: +1 to +4 degrees) after the first transplantation and 5 remained improved after the second cycle. The response rate correlated with the time-intervals between the injections. Conclusion: The results of our study show that repeated intrathecal injections of autologous MSC was safe in patients with ALS and provide indications of medium-term clinical benefits that were related to the intervals between the administrations of the cells. Larger studies are needed to confirm these observations.

Patching Up the Permeability: The Role of Stem Cells in Lessening Neurovascular Damage in Amyotrophic Lateral Sclerosis

“…Overall, 13 patients had a >25% improvement in ALSFRS-R slope and 36.8% of patients showed significant clinical improvement. 177 The administration of SCs overtime showed promising results, and future studies may also examine the therapeutic benefit of stem cells administered to multiple spinal levels, which was very beneficial in a MSC-treated rat model of ALS. 178 Given the multitude of promising results in preclinical stem cell studies for ALS, and the ubiquitous safety reports clinically, future initiatives should aim to enhance the therapeutic benefits of cell-based treatments.…”

Potential of Cellular Therapy for ALS: Current Strategies and Future Prospects

“…Repetitive injections of cells have commonly been used in cellular therapy; for example, repeated injections of autologous bone marrow-derived MSCs (BM-MSCs) are showing no significant adverse events ( Nabavi et al, 2019 ; Siwek et al, 2020 ). A phase II clinical trial with repeated intrathecal administration of BM-MSCs in patients with ALS is safe and well-tolerated ( Petrou et al, 2021 ). Intriguingly, a case report has shown that intraventricular transplantation of autologous BM-MSCs using the Ommaya reservoir in a patient with ALS is safe, and this device has the potential to make repetitive injections of cells more easily ( Baek et al, 2012 ).…”

Stem Cell Therapies in Movement Disorders: Lessons from Clinical Trials

“…Studies in ALS models have suggested that the primary pathophysiological target should be the environment of the motor neuron rather than the motor neuron itself [45]. Studies with different stem cell types in ALS patients have documented variable results over years, but overall, stem cell transplantation may delay ALS progression, improving quality of life (Table 4) [46][47][48][49][50][51][52]. Although multiple molecules (e.g., Vascular endothelial growth factors-VEGF, angiopoietin-related growth factor-ANG, and transforming growth factor beta-TGF-β) have been investigated, we are still missing effective biological markers to predict the efficacy of MSC transplants in patients with ALS [53].…”