Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis

Abstract

BackgroundMultiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system and is one of the leading causes of disability in young adults. Cell therapy is emerging as a therapeutic strategy to promote repair and regeneration in patients with disability associated with progressive MS.MethodsWe conducted a phase I open-label clinical trial investigating the safety and tolerability of autologous bone marrow mesenchymal stem cell-derived neural progenitor (MSC-NP) treatment in 20 patients with progressive MS. MSC-NPs were administered intrathecally (IT) in three separate doses of up to 1 × 107 cells per dose, spaced three months apart. The primary endpoint was to assess safety and tolerability of the treatment. Expanded disability status scale (EDSS), timed 25-ft walk (T25FW), muscle strength, and urodynamic testing were used to evaluate treatment response. This trial is registered with ClinicalTrials.gov, number NCT01933802.FindingsIT MSC-NP treatment was safe and well tolerated. The 20 enrolled subjects completed all 60 planned treatments without serious adverse effects. Minor adverse events included transient fever and mild headaches usually resolving in <24 h. Post-treatment disability score analysis demonstrated improved median EDSS suggesting possible efficacy. Positive trends were more frequently observed in the subset of SPMS patients and in ambulatory subjects (EDSS ≤ 6.5). In addition, 70% and 50% of the subjects demonstrated improved muscle strength and bladder function, respectively, following IT MSC-NP treatment.InterpretationThe possible reversal of disability that was observed in a subset of patients warrants a larger phase II placebo-controlled study to establish efficacy of IT MSC-NP treatment in patients with MS.Funding sourceThe Damial Foundation.

Mesenchymal stem cells: Cell therapy and regeneration potential

“…Stem cell‐based therapies can greatly impact the field of regenerative medicine. MSCs have been used in preclinical and clinical studies to treat degenerative diseases, such as AD (Cui et al, ; Han et al, ; J. Shin et al, ; X. Wang, Ma, et al, ), DDD (Ahn et al, ; Beeravolu et al, ; Pereira et al, ; Perez‐Cruet et al, ), MS (Harris et al, ; Nasri et al, ; Planchon et al, ), PD (Jamali et al, ; H. Kim, Lee, et al, ), and RDD (Mead, Amaral, & Tomarev, ), as summarized in Table . The regenerative mechanisms of transplanted MSCs for these diseases are still unclear; however, some reports have suggested that MSCs have the potential to differentiate or have paracrine effects in vivo (Lee, Choi, Cha, & Hwang, ).…”

“…These dopaminergic neuron cells survived when transplanted into a rat model of PD and displayed greater improvement of behavioral impairments (Y. Wang et al, ). In addition, MSCs have been investigated for the treatment of MS (Harris et al, ; Nasri et al, ; Planchon et al, ). Potential of the MSCs differentiated into neural progenitor cells was investigated to treat MS using a chronic experimental autoimmune encephalomyelitis (EAE) mouse model (Constantinescu, Farooqi, O'Brien, & Gran, ).…”

“…In another similar study, MSCs injected intradiscally into the IVD of the patients resulted in a quick and significant improvement in functionality and in patients experiencing less pain and exhibited less IVD degeneration than the control group (Noriega et al, ). Additionally, a Phase 1 study showed promising therapeutic effects of MSCs for the treatment of MS (Harris et al, ; Planchon et al, ). When MSC‐derived neural progenitor cells were administered intrathecally in three separate doses in the span of 3 months, improvements in muscle strength and functional motor skills were observed (Harris et al, ).…”

“…Additionally, a Phase 1 study showed promising therapeutic effects of MSCs for the treatment of MS (Harris et al, ; Planchon et al, ). When MSC‐derived neural progenitor cells were administered intrathecally in three separate doses in the span of 3 months, improvements in muscle strength and functional motor skills were observed (Harris et al, ). Lastly, MSCs have also been investigated for the treatment of chronic tissue ulcers caused by diabetes.…”

“…It has also been shown that the use of chemokines and cytokines derived from MSCs improved the treatment efficacy for autoimmune disease (M. Wang, Yuan, & Xie, ; Xu, ; W. Zhang, Feng, Pang, Lu, & Wang, ). The interaction between MSCs and the inflammatory niche have the potential to be used for the treatment of many different diseases (Harris et al, ; Xu, ; H. Zhang, Tao, et al, ).…”