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Article Dans Une Revue European Heart Journal Année : 2015

Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience

Philippe Menasche
  • Fonction : Auteur
Valerie Vanneaux
  • Fonction : Auteur
Jean-Roch Fabreguettes
  • Fonction : Auteur
Alain Bel
  • Fonction : Auteur
Lucie Tosca
  • Fonction : Auteur
Sylvie Garcia
Valerie Bellamy
  • Fonction : Auteur
Yohan Farouz
  • Fonction : Auteur
Julia Pouly
  • Fonction : Auteur
Odile Damour
  • Fonction : Auteur
Marie-Cecile Perier
  • Fonction : Auteur
Michel Desnos
  • Fonction : Auteur
Albert A. Hagège
  • Fonction : Auteur
Onnik Agbulut
Patrick Bruneval
Gerard Tachdjian
  • Fonction : Auteur
Jean-Hugues Trouvin
  • Fonction : Auteur
Jerome Larghero
  • Fonction : Auteur

Résumé

Aim This paper describes the multi-step translational approach that has resulted in the generation of clinical-grade human embryonic stem cell-derived cardiac progenitor cells for transplantation in patients with severe ischaemic heart failure. There is now compelling evidence that cells committed to a cardiac lineage are most effective for improving the function of infarcted hearts. This has been confirmed by our pre-clinical studies entailing transplantation of human embryonic stem cell (hESC)-derived cardiac progenitors in rat and non-human primate models of myocardial infarction. These data have paved the way for a translational programme aimed at a phase I clinical trial. Methods and results The main steps of this programme have included (i) the expansion of a clone of pluripotent hESC to generate a master cell bank under good manufacturing practice conditions (GMP); (ii) a growth factor-induced cardiac specification; (iii) the purification of committed cells by immunomagnetic sorting to yield a stage-specific embryonic antigen (SSEA)-1-positive cell population strongly expressing the early cardiac transcription factor Isl-1; (iv) the incorporation of these cells into a fibrin scaffold; (v) a safety assessment focused on the loss of teratoma-forming cells by in vitro (transcriptomics) and in vivo (cell injections in immunodeficient mice) measurements; (vi) an extensive cytogenetic and viral testing; and (vii) the characterization of the final cell product and its release criteria. The data collected throughout this process have led to approval by the French regulatory authorities for a first-in-man clinical trial of transplantation of these SSEA-1(+) progenitors in patients with severely impaired cardiac function. Conclusion Although several facets of this manufacturing process still need to be improved, these data may yet provide a useful platform for the production of hESC-derived cardiac progenitor cells under safe and cost-effective GMP conditions.

Dates et versions

hal-01545444 , version 1 (22-06-2017)

Identifiants

Citer

Philippe Menasche, Valerie Vanneaux, Jean-Roch Fabreguettes, Alain Bel, Lucie Tosca, et al.. Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience. European Heart Journal, 2015, 36 (12), pp.743+. ⟨10.1093/eurheartj/ehu192⟩. ⟨hal-01545444⟩
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