Research

Multiple Sclerosis

Numerous research studies have demonstrated that intravenous stem cell therapy is safe and effective in the treatment of MS. Stem cell therapy has been shown to improve various symptoms associated with MS, reduce rate of relapse and improve quality of life.

Based on the early human clinical trials there appears to be a strong argument for the safe and effective use of intravenous stem cell therapy in the treatment of MS. While we wait for phase II/III trials the current data is encouraging and supports use of stem cell therapy in the clinical setting.

Below we highlight and summarize selected studies demonstrating the safety and efficacy of stem cell therapy in MS. All of the selected studies used intravenous administration but used different cell types and tissue types.

Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis. (Riordan et al, 2018)

In 2018 Riordan et al conducted an open-label, single arm phase I/II study to assess the safety and efficacy of repeated intravenous umbilical cord derived mesenchymal stem cells (UCMSCs) in 20 patients with Multiple Sclerosis (MS). Patients received a total of 7 intravenous infusions over 7 visits which were separated by 1-4 days. 72 adverse events (AEs) were reported with six classified as moderate severity and the remaining as mild. None of the adverse events were deemed ‘definitely’ related to study. The most common AEs were headache and fatigue. There were no serious adverse events and no deaths occurred. Efficacy was assessed using routine standardized assessment tools including the Expanded Disability Status Scale (EDSS), the Scripps Neurological Rating Scale (SNRS), the Nine-Hole Peg Test (9HPT), the 25-Foot Walk Test (25FWT), and the RAND Short Form-36 (SF-36) quality of life (QOL) questionnaire. Patients showed a statistically significant improvement in disability measured by EDSS at 1 month and 1 year follow ups compared to baseline. A statistically significant improvement was seen for the bladder/bowel/sexual dysfunction category of SNRS at 1 month compared to baseline. Patients saw overall improvements in their 9HPT scores with statistically significant improvement in non-dominant hand scores. For 25FWT, all walk times were reduced when compared to baseline at 1 year follow up. A statistically significant improvement was observed in walk times between baseline and 1 month follow up. Patients reported consistent improvements in their quality of life regarding physical, emotional, energy and cognitive symptoms which was sustained at 1 year follow up. MRI was also used to assess changes in lesions and progression of disease. No trends were observed in the number of lesions or disappearance of lesions. 83.3% of patients who completed baseline and follow up MRI showed no disease progression or no new or active lesions. Riordan et al concluded that “We have shown that the intravenous infusion of UCMSC over several days is safe in subjects with MS. Additionally, UCMSC infusions may hold benefits, since this small study group saw improvement in bladder, bowel, and sexual dysfunction, walking, upper extremity physical function, energy and fatigue, general perspective of a positive health change and improved quality of life, and MRI lesions.”

Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis. (Meng et al, 2018)

In 2018 Meng et al conducted a small clinical trial to assess the safety and efficacy of repeated intravenous infusions of umbilical cord derviced mesenchymal stem cells (UCMSCs) in 2 patients with multiple sclerosis (MS). Intravenous infusions were given at 3 month intervals for a total of 7 infusions. Safety was assessed using physiological examination including routine blood, urine and stool tests, electrocardiography, chest xray and frequency and severity of adverse events. All physiological examinations revealed normal indexes. Adverse reactions included fever, dizziness, headache, skin redness and vascular irritation which mainly occurred during infusion. Fever was the most common adverse reaction which resolved without medical intervention within 36 hours. Toxic reactions to treatment were not detected during the 8 year follow up. Efficacy was assessed by changes in symptoms, vital signs, number of clinical attacks, brain MRI and neurological function scores including the Expanded Disability Status Scale (EDSS). Clinical indices were mitigated in two patients after stem cell therapy. The mean annual frequency rate of attacks was remarkably reduced compared to before baseline. Symptoms including unstable walking, coordination ability and balance force were remarkably improved in patient 1. Numbness of right limbs and constipation were mitigated in patient 2. Patient 2 also showed improvements in mental status and memory. EDSS score demonstrated improved clinical symptoms in patient 1 and stable clinical symptoms in patient 2. MRI findings showed that the number of brain foci was reduced suggesting that UCMSC infusion promoted remyelination of nerves. Changes in immune markers were also assessed to evaluate the immunomodulatory effects of UCMSCs. Meng et al found that as the patient’s condition stabilized levels of each marker measured decreased confirming the immunomodulatory properties of UCMSCs. Meng et al concluded that “Our findings confirm that UCMSCs have function of immune regulation and nerve protection, indicating the feasibility of UCMSC transplantation for multiple sclerosis.”

Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study. (Fernandez et al, 2018)

In 2018 Fernandez et al conducted a triple blinded, placebo controlled, randomized phase I/II trial to assess the safety and feasibility of a single intravenous infusion of adipose derived mesenchymal stem cells (ADMSC) in the treatment of patients with advanced secondary progressive multiple sclerosis (SPMS). Nineteen patients receiving stem cell therapy were randomized to receive either low dose or high dose while 11 patients received a placebo which consisted of Ringer’s lactate. The primary objective of this study was to assess safety and feasibility. Safety was assessed by monitoring adverse events (AEs), vital signs, spirometry and standard laboratory measures. A total of 70 AEs were reported during the trial period. The most frequent AEs were urinary tract infections, respiratory infection and anemia. Four serious AEs were reported and none of them were considered to be related to treatment. No tumor formation was reported in the 12 month follow up. There were no significant changes in vital signs, spirometry and laboratory values. However, the low dose group showed a significant decrease in cholesterol and improved kidney function measured by a decrease of creatinine. Efficacy was assessed using numerous measures including expanded disability scale score (EDSS), MRI, evoked potentials, and others. There were no clear effects from stem cell therapy in any of the measurements used to assess efficacy, however this study was not powered to determined efficacy. EDSS values did not show statistically significant change over the study compared to baseline or between groups. In both the low and high dose group brain MRI showed non-statistically significant changes in the number of active lesions compared to baseline. Differences in evoked potentials, which measures electrical activity in different parts of the brain showed trends of efficacy by improved nerve conduction times between treatment groups and control group. Because patients in this study had significantly higher baseline EDSS indicating more advanced disease compared to other similar studies dramatic effects of treatment were not expected by the investigators. Fernandez et al concluded that “the present study demonstrates that infusion of AdMSCs is a safe and feasible procedure in patients with SPMS. Although the study was not powered to determine the efficacy, some hint of efficacy was observed by the use of MRI and evoked potentials.”

Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. (Cohen et al, 2018)

In 2018 Cohen et al conducted an open-label, phase 1 study to assess the feasibility, safety and tolerability of an single intravenous infusion of autologous, culture expanded bone marrow derived mesenchymal stem cells (BMMSCs) in 24 patients with MS. Patients either had relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS). The primary objective was to evaluate the feasibility of culturing stem cells and the safety and tolerability of MSC infusions over 1 month. Secondary objectives included safety and tolerability over 6 months and impact on disease activity measured by MRI at 1 month. Safety was evaluated by assessing adverse events (AEs), vital signs, and various laboratory tests including routine blood tests, immune system markers, and inflammatory markers. Chest Xray and electrocardiogram (EEG) were also performed. There were no severe or serious adverse events related to stem cell therapy. No patients developed clinical or laboratory indications of autoimmune phenomena and none had clinical or radiological evidence of paradoxical disease activation of MS. The most commonly reported adverse events were muscle spasticity, urinary tract infection and fall. Two patients died, 8 and 40 months after stem cell therapy. Both deaths were deemed unrelated to stem cell therapy treatment. Prior to treatment most patients had brain lesions on MRI indicating MS disease activity. After treatment there was no evidence of further activation or inhibition of new/enlarged brain lesions on MRI reflecting no change in disease activity. The lack of inhibition of lesions was surprising to the investigators due to the established anti-inflammatory actions of MSCs. Despite no statistically significant changes in annualized relapse rates during post-infusion follow up period, 75% of patients were free of relapse during the post-infusion follow up period. All relapses, except one, occurred in patients with RRMS. Various exploratory efficacy outcomes were evaluated and were generally stable over the course of the study. These included Multiple Sclerosis Functional Composite (MSFC), 9-hole peg test (9HPT), the 25-Foot Walk Test (25FWT), whole brain MRI outcomes, etc. EDSS scores of most patients were improved from baseline and reflected improvements in ambulation, and cerebral and sensory subsystems. Cohen et al concluded that “this phase 1 trial supports the feasibility, safety and tolerability of autologous MSC transplantation in MS.”

The Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells as a Novel Cellular Therapy for Multiple Sclerosis. (Li et al, 2014)

In 2013 Li et al conducted a randomized, two armed study to assess the safety and efficacy of repeated intravenous human umbilical cord derived mesenchymal stem cells (hUC-MSC) in addition to conventional treatment in 13 patients with MS. Patients either had relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS). Thirteen patients in treatment group received an intravenous infusion of stem cells every two weeks for three consecutive times. Ten patients in control group only received conventional treatment consisting of anti-inflammatory and immunosuppressant medication. The follow up period was 12 months post-treatment. Safety assessment included physical examination, adverse events and quarterly brain MRI. The clinical safety was demonstrated without any reported significant adverse effects during 12 month follow up. Brain MRI results were not discussed in results section. Efficacy was evaluated by assessing change in neurological function using the Expanded Disability Scale Score (EDSS) and occurrence of relapse. EDSS values were significantly lower in the treatment group throughout the study and at 12 month follow up indicating decreased neurological disability. Patients in the treatment group also had a more stable disease course and had significantly fewer incidences of relapse compared to control group at 12 month follow up. Immune signaling markers known as cytokines were also assessed to evaluate the anti-inflammatory and immunomodulatory properties of hUC-MSC therapy. Anti-inflammatory markers including IL-4 and IL-10 increased remarkably while pro-inflammatory markers including IL-17 and TNF-alpha decreased significantly in the treatment group. Hepatocyte Growth Factor (HGF) which is involved with immune modulation and tissue regeneration, and IFN-gamma which is involved with modulating the immune system were also found to be increased in the treatment group. Li et al concluded that “During a 1-year observation, no significant adverse effects were found, indicating the clinical safety could be well accepted. The significantly lower relapse occurrence and EDSS scores were found in the experimental group compared to the control group.” “Our study contributed, in part, to providing more evidence for the potential of hUC-MSCs as a therapy for MS.”

Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. (Llufriu et al, 2014)

In 2014 Llufriu et al conducted a randomized, double blind, crossover placebo controlled phase II trial investigating the efficacy of a single intravenous infusion of bone marrow derived mesenchymal stem cells (BMMSCs) in 9 patients with relapsing remitting multiple sclerosis (RRMS). After 6 months post initial infusion patients crossed over and received the other treatment and were followed for another 6 months. The primary objective of this study was to determine safety and efficacy in terms of cumulative number of brain lesions. All reported adverse events (AEs) were graded as mild and were deemed not to be related to treatment. No serious adverse events were reported during the study or at 12 month follow up. Delayed AEs were also not observed. At 6 and 12 months patients in treatment group demonstrated a lower accumulate number of lesions compared to baseline, although not statistically significant. Secondary endpoints included clinical outcomes measured by the Expanded Disability Scale Score (EDSS) and MS Functional Composite (MSFC), brain MRIs and others. Immunological tests were also evaluated to assess immunomodulatory effects. No significant treatment differences were observed in any of the secondary endpoints. However, there were non-statistically significant differences in immune markers consistent with a lower pro-inflammatory profile in patients treated with MSCs. Llufriu et al concluded that “Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties.”

SOURCES:

• https://www.nationalmssociety.org/nationalmssociety/media/msnationalfiles/brochures/brochure-just-the-facts.pdf
• https://www.nationalmssociety.org/What-is-MS/MS-FAQ-s#question-How-many-people-have-MS
• Rice, C. M., Marks, D. I., Walsh, P., Kane, N. M., Guttridge, M. G., Redondo, J., … Scolding,N. J. (2015). Repeat infusion of autologous bone marrow cells in multiple sclerosis: protocol for a phase I extension study (SIAMMS-II). BMJ Open, 5(9), e009090. https://doi.org/10.1136/bmjopen-2015-009090
• Hou, Z. L., Liu, Y., Mao, X. H., Wei, C. Y., Meng, M. Y., Liu, Y. H., … Xiao, Z. C. (2013). Transplantation of umbilical cord and bone marrow-derived mesenchymal stem cells in a patient with relapsing-remitting multiple sclerosis. Cell Adhesion and Migration, 7(5), 404–407. https://doi.org/10.4161/cam.26941
• Riordan, N. H., Morales, I., Fernández, G., Allen, N., Fearnot, N. E., Leckrone, M. E., … Paz Rodriguez, J. (2018). Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis. Journal of Translational Medicine, 16(1). https://doi.org/10.1186/s12967-018-1433-7
• Meng, M., Liu, Y., Wang, W., Wei, C., Liu, F., Du, Z., … Li, Q. (2018). Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis. American Journal of Translational Research, 10(1), 212 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801359/
• Fernández, O., Izquierdo, G., Fernández, V., Leyva, L., Reyes, V., Guerrero, M., … Research Group Study EudraCT 2008-004015-35. (2018). Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study. PloS One, 13(5), e0195891. https://doi.org/10.1371/journal.pone.0195891
• Cohen, J. A., Imrey, P. B., Planchon, S. M., Bermel, R. A., Fisher, E., Fox, R. J., … Lazarus, H. M. (2018). Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England), 24(4), 501–511. https://doi.org/10.1177/1352458517703802
• Li, J.-F., Zhang, D.-J., Geng, T., Chen, L., Huang, H., Yin, H.-L., … Wang, Y.-L. (2014). The Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells as a Novel Cellular Therapy for Multiple Sclerosis. Cell Transplantation, 23(1_suppl), 113–122. https://doi.org/10.3727/096368914×685005
• Llufriu, S., Sepúlveda, M., Blanco, Y., Marín, P., Moreno, B., Berenguer, J., … Saiz, A. (2014). Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS ONE, 9(12). https://doi.org/10.1371/journal.pone.0113936