Beneficial Effects of Autologous Mesenchymal Stem Cell Transplantation in Active Progressive Multiple Sclerosis

Panayiota Petrou; Ibrahim Kassis; Netta Levin; Friedemann Paul; Yael Backner; Tal Benoliel; Frederike Cosima Oertel; Michael Scheel; Michelle Hallimi; Nour Yaghmour; Tamir Ben Hur; Ariel Ginzberg; Yarden Levy; Oded Abramsky; Dimitrios Karussis


Brain. 2020;143(12):3574-3588. 

In This Article

Abstract and Introduction


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.


Mesenchymal stem cells (MSCs) are non-haematopoietic stromal cells that reside mainly in the bone marrow compartment, but also in fat and other tissues. Their classical role is to support haematopoiesis and produce cells of the mesodermal lineage (Pittenger et al., 1999; Lennon and Caplan, 2006). Studies have described additional MSC properties, including immunomodulatory and neurotrophic effects (Caplan, 1991; Woodbury et al., 2000; Orlic et al., 2001; Blondheim et al., 2006; Caplan and Dennis, 2006; Kassis et al., 2006, 2008, 2011; Uccelli et al., 2007, 2008). In animal models, intravenous and intrathecal administration of MSCs has been shown to suppress experimental autoimmune encephalomyelitis (EAE) (Zappia et al., 2005; Kassis et al., 2008; Harris et al., 2012) and support remyelination following spinal trauma or induced demyelination (Cizkova et al., 2006; Zhang et al., 2010; Hedayatpour et al., 2013).

Few small, mostly open-label, clinical trials have reported indications of favourable effects of MSC treatment in stroke, multi-system atrophy, multiple sclerosis, and amyotrophic lateral sclerosis (Karussis et al., 2010; Yamout et al., 2010; Connick et al., 2012; Lee et al., 2012; Llufriu et al., 2014; Lublin et al., 2014a; Harris et al., 2016, 2018; Petrou et al., 2016; Cohen et al., 2018; ,Fernandez et al., 2018; Riordan et al., 2018). Whether the observed benefits were mediated by immunomodulatory mechanisms or by neurotrophic and neuroprotective effects remains controversial.

These earlier studies prompted us to perform a controlled clinical trial to examine the therapeutic efficacy of MSC transplantation in progressive multiple sclerosis, for which (at least for the subtype without activity) there is a critical unmet need for treatment. We also aimed to investigate the most favourable route of cell delivery.

We present here the results of this double-blind trial that compared the clinical effects of intravenous or intrathecal injections of autologous bone marrow-derived MSCs (1 × 106/kg) with those of sham injections, in 48 patients with active or worsening progressive multiple sclerosis.