Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study

Abstract

SummaryBackgroundMore than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis.MethodsPatients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5–6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200.FindingsWe isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×106 cells per kg bodyweight (range 1·1–2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3–4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change −0·02 logMAR units, 95% CI −0·03 to −0·01; p=0·003) and visual evoked response latency (−1·33 ms, −2·44 to −0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm2, 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio.InterpretationAutologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection.FundingMedical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.

The Use of Mesenchymal Stem Cells in the Treatment of Multiple Sclerosis: An Overview of Open Labels and Ongoing Studies

“…T1 hypointense lesion volume decreased after treatment and magnetization transfer ratio increased, but these changes were no longer statistically significant. These findings could provide indirect support for this idea that MSC can promote re-myelination and can have a neuroprotective effect [49].…”

Transdifferentiation of autologous bone marrow cells on a collagen-poly(ε-caprolactone) scaffold for tissue engineering in complete lack of native urothelium

“…At present, in vitro and in vivo studies have demonstrated that MSCs can differentiate beyond mesodermal lineages and into endodermal and ectodermal lineages [6][7][8][9]. In addition, isolation of MSCs from bone marrow is a well-established method accredited with standards for good manufacturing practice and is currently used in clinical trials [36][37][38].…”

“…MSCs were isolated from bone marrow aspirates from the iliac crest of healthy volunteer adult donors (age [37][38][39][40]. The Hospital Ethics Committee approved cell harvesting of UCs and informed consent was given by the parents.…”

Stem cells: Stemming the tide

“…A few phase I studies have shown that these cells are safe 7 , and researchers are now looking for signs of efficacy in larger phase II trials. Freedman, for example, is collaborating with colleagues to enrol 40 patients with either relapsing-remitting or secondary progressive MS into a Canadian trial called MESCAMS.…”