title: Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study.
abstract: BACKGROUND
  More 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.
  
  
  METHODS
  Patients 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.
  
  
  RESULTS
  We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) 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 mm(2), 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.
  
  
  CONCLUSIONS
  Autologous 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.
  
  
  BACKGROUND
  Medical 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.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Connick
authors.forename: Madhan
authors.initials: M
authors.lastname: Kolappan
authors.forename: Charles
authors.initials: C
authors.lastname: Crawley
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Webber
authors.forename: Rickie
authors.initials: R
authors.lastname: Patani
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Michell
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Du
authors.forename: Shi-Lu
authors.initials: SL
authors.lastname: Luan
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Altmann
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Michael A
authors.initials: MA
authors.lastname: Scott
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
mesh_terms: D000328:Adult; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index; D014182:Transplantation, Autologous / Q000009:adverse effects / Q000379:methods*; D016896:Treatment Outcome; D014786:Vision Disorders / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology