Randomized Placebo-Controlled Phase II Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis

Abstract

ObjectiveUncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study.MethodsPatients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0–6.5 were randomized to receive IV 1–2×106 bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects.ResultsAt baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1–8.8 vs 12.3, 95% CI = 4.4–34.5, p = 0.064), and at the end of study to reduced mean GEL (−2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients.ConclusionBone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties.ClinicalTrials.gov NCT01228266

Stem Cell Therapies in Clinical Trials: Progress and Challenges

“…However, another study showed a decrease in endoscopic active luminal CD (42%) in 7/15 patients given 2 million MSCs/kg (Forbes et al, 2014), suggesting that there may be clinical benefits of MSC therapy for CD. Likewise, intrathecal or intravenous injections of MSCs have been tried for advanced progressive and relapsing and remitting MS, with little detectable clinical benefit (Bonab et al, 2012;Connick et al, 2012;Llufriu et al, 2014;Yamout et al, 2010). There were some indications of minor reductions in MRI inflammatory parameters in the relapsing and remitting type of MS (Llufriu et al, 2014).…”

Optical coherence tomography findings in Huntington’s disease: a potential biomarker of disease progression

“…In the past 15 years, the potential role of optical coherence tomography (OCT) measurements as biomarkers of disease progression in neurodegenerative disorders, particularly multiple sclerosis, Alzheimer's disease, neuromyelitis optica and Parkinson's disease, has been widely investigated [14][15][16][17][18][19][20][21][22][23][24]. OCT measurements are frequently used in observational studies, clinical practice and, more recently, therapeutic trials, with the number of studies in this area increasing exponentially over the last 5 years [21,25].…”

“…OCT measurements are frequently used in observational studies, clinical practice and, more recently, therapeutic trials, with the number of studies in this area increasing exponentially over the last 5 years [21,25].…”

The transplantation of mesenchymal stem cells derived from unconventional sources: an innovative approach to multiple sclerosis therapy

“…It was found that patients gained a relative recovery in their optic nerve without significant side effects. In a recent randomized placebocontrolled phase II trial (Llufriu, Sepulveda et al 2014) involving 9 relapsing-remitting MS patients who failed to Zappia et al (2005) Human BM Production of neurotrophic factors, such as BDNF Neurological recovery and oligodendrogenesis improvement, demyelination, and infiltration decrease Zhang et al (2005) Mouse BM Downregulation of IL-6, T-bet, RORγT and Foxp3…”