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

Panayiota Petrou ,Ibrahim Kassis ,Ariel Ginzberg ,Nour Eddine Yaghmour ,Dimitrios Karussis

doi:10.52586/4980

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a degenerative disease affecting the motor neurons in brain and spinal cord with a rapidly progressive course, leading to generalized muscle paralysis and death, usually within 3–5 years from onset
To evaluate the prognostic factors in the included patients, we calculated the rate of progression in ALSFRSR from the onset of symptoms till the enrollment to the study or till the first Mesenchymal stem cells (MSC)-treatment
We did not observe any serious side effects related to the treatment. 1 patient had aspiration pneumonia after the bone marrow aspiration (BMA), 1 suffered a fracture of the ankle, 1 had renal colic/urolithiasis, all of them not related to the treatment with MSC. 3 patients suffered from headache and back pain after the stem cells injection, related to the lumbar puncture and 1 patient suffered from general weakness and fatigue for two weeks post MSC injection, possibly related to the treatment

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a degenerative disease affecting the motor neurons in brain and spinal cord with a rapidly progressive course, leading to generalized muscle paralysis and death, usually within 3–5 years from onset. No therapy has shown sufficient efficacy in halting the progression of the disease. The two FDA approved therapies, Riluzole and Edravarone showed a mild to moderate effect in terms of reduction of the rate of progression and prolongation of survival by few months [1, 2]. Stem cells in general, were shown to induce neuroprotection and immunomodulation, by secreting growth factors and immunomodulatory cytokines, and by increasing the regulatory T cells [3,4,5,6,7,8,9,10]. Mesenchymal stem cells (MSC) are non-hematopoietic stromal cells, which can be obtained from various sources, i.e., bone marrow (BM-MSC), adipose tissue (AT-MSC), embryonic tissue (E-MSC), cord blood (CB-MSC), reprogramming of mature cells (iMSC) and perinatal tissue-Wharton’s jelly (WJMSC) [11] and amniotic membrane [12]

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Conclusion