The blinding lights of ‘Mesenchymal Stem Cell Transplantation’


Recently, the first phase II double-blinded trial of mesenchymal stem cell (MSC) transplantation in MS was published. MSC reside mainly in the bone marrow compartment. These stem cells can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat tissue). They do not evolve into immune cells. To harvest the MSC, a bone marrow puncture (mostly done at hip crest level) is performed. How MSC exactly impact on the disease course/activity in MS is not known. Based on animal data, it is hypothesised they have a neuroprotective effect by the production of growth factors and work immunomodulatory by downregulating B and T cell responses.

In the trial, 48 individuals with progressive MS were randomised to 1. Intrathecally administered MSC (through a lumbar puncture), 2. Intravenously administered MSC (infusion) or 3. Placebo for a 6 month time period. As this was a double-blinded trial, all people receiving the MSC intravenously also had to undergo a lumbar puncture and vice versa. After 6 months, half of the participants receiving intrathecal MSC stayed on this type of treatment while the other half moved on to placebo. A similar strategy was applied in the other trial arms. 

The primary outcome of this trial was a confirmed increase in EDSS: 1 point in EDSS for patients with baseline scores ≤ 5.0 and 0.5 points for baseline EDSS >5.0. In pwMS receiving intrathecal MSC transplantation 6.7% reached this outcome, 9.7% for intravenous MSC and 41.9% on placebo. This is a very impressive result, especially given the short time frame of the study. The study also analysed many secondary outcomes such 25-Foot-Walk-Test, 9-Hole-Peg-Test, functional MRI imaging, cognitive scores etc. with a variable favourable effect of MSC transplantation. Interestingly, there was no significant effect of MSC transplantation on the number of contrast-enhancing lesions and no effect on brain volume loss. 

 Some reflections on this trial:

  • This is a single-center trial conducted in one hospital in Israel. This setting automatically limits the potential of blinding the results and trial outcomes. What applies to stem cells does not apply to the neurology department: the number of physicians devoted to MS and the conduction of this trial in one hospital is not self-renewing but finite. Especially as harvesting the stem cells and preparing them for medical use in the lab is a time-consuming, costly process, it is not unimaginable that the individuals involved in conducting this trial and potentially rating the patients might have had their unconscious suspicions on who was on active versus placebo treatment.  In addition, it has been shown over and over that EDSS is prone to inter-rater variability (read: EDSS can be 5.5 or 6.0 based on the subjective judgement of the rater). Unfortunately, the results of MSC transplantation on the more objective outcome measures such as contrast-enhancing lesions on MRI were less convincing. Moreover, also the results for other quantifiable measures such as retinal fibre density measured by optical coherence tomography were not compelling (only significant in the left eye).
  • It is undeniable that the pwMS included in both placebo and treatment arms of this trial were very active. People in the placebo group had a median increase in EDSS of 0.24 points at 3 months and 0.3 at 6 months. The decimal points in these EDSS scores mistakenly imply that the associated clinical changes are modest. Nonetheless, increasing from 6 to 6.5 signifies that your walking range with unilateral support goes from more than 50 m to less than 50 m. Natural history studies showed that pwMS remain on average 4.7 years on each EDSS level if they have reached an EDSS between 4 and 6. Moreover, the cohort seems to have been enriched for progressive pwMS with a high burden of contrast-enhancing lesions. Some pwMS in the intravenous MSC transplant group had 8 contrast-enhancing lesions which is definitely exceptional. 

Overall, the results are interesting but the fact they are originating from a single center trial including a very active progressive MS population warrants caution about the generalisability. In addition, it is unclear whether a long-lasting effect of this costly treatment is to be expected. As this song is about the difficulty of resisting temptations – in this case the very much wanted prospect of an effective therapy in progressive MS, it might provide consolation for the post-blogpost-blues:

Twitter: @SmetsIde

Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis

Panayiota Petrou 1, Ibrahim Kassis 1, Netta Levin 2, Friedemann Paul 3 4 5, Yael Backner 2, Tal Benoliel 2, Frederike Cosima Oertel 3 4, Michael Scheel 3 4 6, Michelle Hallimi 1, Nour Yaghmour 1, Tamir Ben Hur 2, Ariel Ginzberg 1, Yarden Levy 1, Oded Abramsky 2, Dimitrios Karussis 1Affiliations expand

  • PMID: 33253391
  • DOI: 10.1093/brain/awaa333


In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0-6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P < 0.0001 and P < 0.0048, respectively). MSC-IT transplantation induced additional benefits on the relapse rate, on the monthly changes of the T2 lesion load on MRI, and on the timed 25-foot walking test, 9-hole peg test, optical coherence tomography, functional MRI and cognitive tests. Treatment with MSCs was well-tolerated in progressive multiple sclerosis and induced short-term beneficial effects regarding the primary end points, especially in the patients with active disease. The intrathecal administration was more efficacious than the intravenous in several parameters of the disease. A phase III trial is warranted to confirm these findings.

Keywords: mesenchymal stromal cells (MSC); multiple sclerosis; neuro-regeneration; neuroprotection; stem cells.

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