Research

Amyotrophic Lateral Sclerosis (ALS)

Despite the progress in understanding the pathophysiology of ALS and advances in treatment there is still no efficient treatment for the neuro-degeneration observed in ALS. Stem cell therapy has been shown to be safe and have clinical benefits in patients with ALS.

A small randomized, controlled trial by Oh et al demonstrated that repeated intrathecal injections of bone marrow derived mesenchymal stem cells (BMMSCs) showed sustained clinical benefits and were deemed safe in patients with ALS. Patients who received stem cell therapy in addition to conventional treatment showed significantly greater functional stability measured by Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) at 4 and 6 months after treatment. At 4 month follow up, 97% of patients who received stem cell therapy had over 75% improvement. This effect decreased but was sustained at 6 months with 78% of patients having over 75% improvement. This effect was not seen in control group who only received conventional therapy. Patients in the stem cell therapy group also showed significantly decreased pro-inflammatory markers and increased anti-inflammatory markers. The overall incidence of adverse events during the study and follow up period were not significantly different between treatment and control group. There were no treatment related adverse events or serious adverse events. Oh et al concluded that “this study provides preliminary evidence that 2 repeated intrathecal, autologous BM-MSC injections are safe and effective in reducing the decline of ALSFRS-R for at least 6 months.”

• Oh, K. W., Noh, M. Y., Kwon, M. S., Kim, H. Y., Oh, S. il, Park, J., … Kim, S. H. (2018). Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis. Annals of Neurology, 84(3), 361–373. https://doi.org/10.1002/ana.25302

In a prospective, phase I/IIa trial by Sykova et al treatment with intrathecal bone marrow derived mesenchymal stem cells (BMMSCs) was found to be safe and showed clinical improvement in functional status, respiratory function and muscle strength in patients with ALS. No suspected or unexpected serious adverse events were observed during the follow up period. Headaches post treatment were commonly reported but expected. Functional status measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was significantly improved at 3 months in patients who received stem cell therapy. Patients also showed a significant slow down of disease at 3, 6 ,9 and 12 months after treatment. Respiratory function as measured by forced vital capacity (FVC) remained stable for 80% of patients at 9 months and 60% of patients at 12 months. Muscle strength remained stable in 75% of patients 3 month after treatment. Sykova et al concluded that “Our results demonstrate that the intrathecal application of BM-MSCs in ALS patients is a safe procedure and suggest that it is able, at least temporarily, to slow down the progression of the disease.”

• Syková, E., Rychmach, P., Drahorádová, I., Konrádová, Ši., Růžičková, K., Voříšek, I., … Bojar, M. (2017). Transplantation of Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial. Cell Transplantation. https://doi.org/10.3727/096368916×693716

In a small open label, phase 2 trial Glass et al showed that repeated intraspinal injections of human spinal cord derived neural stem cells at escalating doses was safe in patients with ALS. This study was not designed to determine efficacy of treatment. The majority of observed adverse events was related to surgical procedure of administering stem cells and included pain at the incision site and transient paresthesias. The second most common adverse events were related to immunosuppressive medications. Two patients incurred serious complications after treatment however the causes are debatable with surgical trauma and inflammatory reaction to stem cells as possibilities. Glass et al concluded that “the injection procedure, as well as the introduction of high doses of HSSCs into the spinal cord, is relatively safe.”

• Glass, J. D., Hertzberg, V. S., Boulis, N. M., Riley, J., Federici, T., Polak, M., … Feldman, E. L. (2016). Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials. Neurology. https://doi.org/10.1212/WNL.0000000000002889

In 2016 Petrou et al conducted a phase 1/2 open-label proof of concept study and a phase 2a dose-escalation study to investigate the safety and efficacy of intramuscular and or intrathecal injection of mesenchymal stem cell neurotrophic growth factors (MSC-NTF) in patients with early and late stage ALS. The treatment and both routes of administration were found to be safe and well tolerated over the study and follow up period. There were no treatment related serious adverse events and most of the reported adverse events were mild and transient. The most common adverse events were headache, fever, vomiting, leg and back pain and neck stiffness. Functional status measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale- Revised score (ALSFRS-R) was significantly reduced compared to baseline in both studies. Respiratory function measured by forced vital capacity (FVC) was increased only in patients who received intrathecal injection. 87% of patients were defined as responders to treatment having at least 25% improvement 6 months after treatment. 67% of patients had more than 50% improvement during this follow up period. Petrou et al concluded that “The results suggest that IT and IM administration of MSC-NTF cells in patients with ALS is safe and provide indications of possible clinical benefits, to be confirmed in upcoming clinical trials.”

Petrou, P., Gothelf, Y., Argov, Z., Gotkine, M., Levy, Y. S., Kassis, I., … Karussis, D. (2016). Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2015.432

A phase 1 open-label clinical trial by Mazzini et al demonstrated that microinjections of human neural stem cells into the lumbar cord tract were safe and well tolerated with trends towards clinical improvement in non-ambulatory patients with sporadic ALS. There were no severe adverse events and no post-surgery respiratory difficulties. The most common adverse event was post-surgical pain reported immediately after surgery. 30% of patients showed a transitory improvement in the ambulation sub score of the Amyotrophic Lateral Sclerosis Functional Rating Scale- Revised score (ALSFRS-R). Mazzini et al concluded that “it appears that transplantation of human fetal neural cells in the lumbar spinal cord is a safe procedure.”

• Mazzini, L., Gelati, M., Profico, D. C., Sgaravizzi, G., Projetti Pensi, M., Muzi, G., … Vescovi, A. L. (2015). Human neural stem cell transplantation in ALS: Initial results from a phase I trial. Journal of Translational Medicine, 13(1). https://doi.org/10.1186/s12967-014-0371-2