Safety and Immunological Effects of Mesenchymal Stem Cell Transplantation in Patients With Multiple Sclerosis and Amyotrophic Lateral Sclerosis

Abstract

To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Design: A phase 1/2 open-safety clinical trial. Patients: Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled. Intervention: After culture, a mean (SD) of 63.2ϫ 10 6(2.5ϫ10 6 ) MSCs was injected intrathecally (n =34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex). Main Outcome Measures:The main outcome measure was the recording of side effects. Follow-up (Յ25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation.Results: Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4 ϩ CD25 ϩ regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40 ϩ , CD83 ϩ , CD86 ϩ , and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation. Conclusion:Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects.

Cell Therapy for Multiple Sclerosis

“…However, this clinical experience opened the way for a trial of BMSC transplantation in MS. As previously discussed, the rationale for BMSC therapy was to exploit their immunomodulatory and trophic properties in a CNStargeted manner. In a phase I/II open-safety clinical trial [287], BMSC were delivered intravenously and intrathecally into patients with chronic MS that had failed conventional treatments, and to patients with amyotrophic lateral sclerosis. There were transient side effects of headache and low grade fever, attributable to meningeal irritation, but no major side effects.…”

Magnetic Resonance Imaging of Single Co-Labeled Mesenchymal Stromal Cells after Intracardial Injection in Mice

“…Several studies show their positive impact on wound healing, bone, cartilage and tendon repair in clinical settings [24 -27]. Recently, Karussis et al showed that transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects [28]. Even though MSC are known to deliver local growth factors for the regulation of hematopoesis, the exact mechanism of their positive modulatory impact in peripheral organs after either local or systemic application remains unclear [29 -31].…”

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

“…Of note, it seems that autologous BM-MSCs derived from the bone marrow of MS patients showed the same properties of allogenic BMMSCs derived from healthy donors, as regard to proliferation, phenotype, and differentiation in vivo and immunosuppressive activity ). According to a phase 1/2 open-safety clinical trial of 2010 (Karussis et al 2010), the intravenous and intrathecal transplantation of autologous BM-MSCs (60-70 × 10 6 ) obtained from the patient's bone marrow and transplanted in 15 MS patients is a clinically feasible and relatively safe procedure, which induces immediate immunomodulatory effects. No significant adverse effects in one-year follow-up were recorded, except for a headache and fever in those patients intrathecally injected.…”