title: Evaluation of the safety and tolerability of a high-dose intravenous infusion of allogeneic mesenchymal precursor cells.
abstract: OBJECTIVE
  Over the past decade, mounting evidence has shown that mesenchymal stromal cells have the potential to exert protective and reparative effects in a variety of disease settings. Clinical trials are being increasingly established to investigate the therapeutic potential of these cells; however, several safety concerns remain to be addressed, of which dosage safety for intravenous administration is paramount. Published safety studies thus far have predominantly been carried out in small-animal models, whereas data for high-dose allogeneic intravenous administration in large-animal models are limited. This study investigates the safety and tolerability of a single high-dose intravenous infusion of 450 million allogeneic ovine mesenchymal precursor cells (oMPCs) in adult sheep.
  
  
  METHODS
  Allogeneic oMPCs (n = 450 million) were intravenously administered to 2-year-old castrated male sheep through the use of three different infusion rates. Sheep were intensively monitored for 7 days by means of vital physiological observations (temperature, blood pressure, heart rate, respiratory rate and oxygen saturation) as well as venous and arterial blood analysis. In addition, full post mortem examination was performed in all animals.
  
  
  RESULTS
  A single high dose of intravenously administered cells was well tolerated, with no serious adverse effects reported. No physiologically significant changes in vital signs, oxygen saturation, blood gas analysis or clinical pathology were observed over the duration of the study.
  
  
  CONCLUSIONS
  Intravenous delivery of a single high-dose infusion of oMPCs is well tolerated in a large animal model. This study provides additional safety evidence for their intravenous use in future human clinical trials.
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, Australia.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: McDonald
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Oehme
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, Australia.
authors.forename: Yen
authors.initials: Y
authors.lastname: Pham
authors.affiliation: Mesoblast Ltd, Melbourne, Victoria, Australia.
authors.forename: Kilian
authors.initials: K
authors.lastname: Kelly
authors.affiliation: Mesoblast Ltd, Melbourne, Victoria, Australia.
authors.forename: Silviu
authors.initials: S
authors.lastname: Itescu
authors.affiliation: Monash Animal Services, Monash University, Clayton, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Gibbon
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia. Electronic address: graham.jenkin@monash.edu.
authors.forename: Graham
authors.initials: G
authors.lastname: Jenkin
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D012756:Sheep; D014184:Transplantation, Homologous
keywords: clinical translation; dosage; mesenchymal stromal/precursor cells; safety; stem cell therapy