Sickle cell disease is characterized by chronic anaemia and vaso-occlusive crises, which eventually lead to multi-organ damage and premature death. Haematopoietic stem cell transplantation is the only curative treatment but it is limited by toxicity and poor availability of HLA-compatible donors. A gene therapy approach based on the autologous transplantation of lentiviral-corrected haematopoietic stem and progenitor cells was shown to be efficacious in one patient. However, alterations of the bone marrow environment and the red blood cells' properties hamper the harvesting and immunoselection of patient stem cells from bone marrow. The use of Filgrastim to mobilize large numbers of haematopoietic stem and progenitor cells (HSPC) in the circulation has been associated with severe adverse events in sickle cell patients. Thus, broader application of the gene therapy approach requires the development of alternative mobilization methods. We set up a Phase I/II clinical trial whose primary objective was to assess the safety of a single injection of Plerixafor in sickle cell patients under RBC exchanges to decrease Haemoglobin S level below 30%. The secondary objective was to measure the efficiency of HSPC mobilization and isolation. No adverse events were observed. Large numbers of CD34+ cells were mobilized extremely quickly. Importantly, the mobilized cells contained high numbers of haematopoietic stem cells, expressed high levels of stemness genes, and engrafted very efficiently in immunodeficient mice. Thus, Plerixafor can be safely used to mobilize haematopoietic stem cells in sickle cell patients; this finding opens up new avenues for treatment approaches based on gene addition and genome editing.

Plerixafor enables the safe, rapid, efficient mobilization of haematopoietic stem cells in sickle cell disease patients after exchange transfusion / Lagresle-Peyrou, Chantal; Lefrère, François; Magrin, Elisa; Ribeil, Jean-Antoine; Romano, Oriana; Weber, Leslie; Magnani, Alessandra; Sadek, Hanem; Plantier, Clémence; Gabrion, Aurélie; Ternaux, Brigitte; Félix, Tristan; Couzin, Chloé; Stanislas, Aurélie; Tréluyer, Jean-Marc; Lamhaut, Lionel; Joseph, Laure; Delville, Marianne; Miccio, Annarita; André-Schmutz, Isabelle; Cavazzana, Marina. - In: HAEMATOLOGICA. - ISSN 0390-6078. - 103:5(2018), pp. 778-786. [10.3324/haematol.2017.184788]

Plerixafor enables the safe, rapid, efficient mobilization of haematopoietic stem cells in sickle cell disease patients after exchange transfusion

Romano, Oriana;Miccio, Annarita;
2018

Abstract

Sickle cell disease is characterized by chronic anaemia and vaso-occlusive crises, which eventually lead to multi-organ damage and premature death. Haematopoietic stem cell transplantation is the only curative treatment but it is limited by toxicity and poor availability of HLA-compatible donors. A gene therapy approach based on the autologous transplantation of lentiviral-corrected haematopoietic stem and progenitor cells was shown to be efficacious in one patient. However, alterations of the bone marrow environment and the red blood cells' properties hamper the harvesting and immunoselection of patient stem cells from bone marrow. The use of Filgrastim to mobilize large numbers of haematopoietic stem and progenitor cells (HSPC) in the circulation has been associated with severe adverse events in sickle cell patients. Thus, broader application of the gene therapy approach requires the development of alternative mobilization methods. We set up a Phase I/II clinical trial whose primary objective was to assess the safety of a single injection of Plerixafor in sickle cell patients under RBC exchanges to decrease Haemoglobin S level below 30%. The secondary objective was to measure the efficiency of HSPC mobilization and isolation. No adverse events were observed. Large numbers of CD34+ cells were mobilized extremely quickly. Importantly, the mobilized cells contained high numbers of haematopoietic stem cells, expressed high levels of stemness genes, and engrafted very efficiently in immunodeficient mice. Thus, Plerixafor can be safely used to mobilize haematopoietic stem cells in sickle cell patients; this finding opens up new avenues for treatment approaches based on gene addition and genome editing.
103
5
778
786
Plerixafor enables the safe, rapid, efficient mobilization of haematopoietic stem cells in sickle cell disease patients after exchange transfusion / Lagresle-Peyrou, Chantal; Lefrère, François; Magrin, Elisa; Ribeil, Jean-Antoine; Romano, Oriana; Weber, Leslie; Magnani, Alessandra; Sadek, Hanem; Plantier, Clémence; Gabrion, Aurélie; Ternaux, Brigitte; Félix, Tristan; Couzin, Chloé; Stanislas, Aurélie; Tréluyer, Jean-Marc; Lamhaut, Lionel; Joseph, Laure; Delville, Marianne; Miccio, Annarita; André-Schmutz, Isabelle; Cavazzana, Marina. - In: HAEMATOLOGICA. - ISSN 0390-6078. - 103:5(2018), pp. 778-786. [10.3324/haematol.2017.184788]
Lagresle-Peyrou, Chantal; Lefrère, François; Magrin, Elisa; Ribeil, Jean-Antoine; Romano, Oriana; Weber, Leslie; Magnani, Alessandra; Sadek, Hanem; Plantier, Clémence; Gabrion, Aurélie; Ternaux, Brigitte; Félix, Tristan; Couzin, Chloé; Stanislas, Aurélie; Tréluyer, Jean-Marc; Lamhaut, Lionel; Joseph, Laure; Delville, Marianne; Miccio, Annarita; André-Schmutz, Isabelle; Cavazzana, Marina
File in questo prodotto:
File Dimensione Formato  
Lagresle-Peyrou et al. - 2018 - Haematologica.pdf

accesso aperto

Tipologia: Versione dell'editore (versione pubblicata)
Dimensione 1.22 MB
Formato Adobe PDF
1.22 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1246330
Citazioni
  • ???jsp.display-item.citation.pmc??? 31
  • Scopus 68
  • ???jsp.display-item.citation.isi??? 62
social impact