Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia.
Sarah MarktelSamantha ScaramuzzaMaria Pia CicaleseFabio GiglioStefania GalimbertiMaria Rosa LidonniciValeria CalbiAndrea AssanelliMaria Ester BernardoClaudia RossiAndrea CalabriaRaffaella MilaniSalvatore GattilloFabrizio BenedicentiGiulio SpinozziAnnamaria AprileAlessandra BergamiMiriam CasiraghiGiulia ConsiglieriNicoletta MaseraEmanuela D'AngeloNadia MirraRaffaella OrigaImmacolata TartaglioneSilverio PerrottaRobert WinterMilena CoppolaGianluca ViarengoLuca SantoleriGiovanna GraziadeiMichela GabaldoMaria Grazia ValsecchiEugenio MontiniLuigi NaldiniMaria Domenica CappelliniFabio CiceriAlessandro AiutiGiuliana FerrariPublished in: Nature medicine (2019)
ß-thalassemia is caused by ß-globin gene mutations resulting in reduced (β+) or absent (β0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express ß-globin represents a potential therapeutic option. We treated three adults and six children with ß0 or severe ß+ mutations in a phase 1/2 trial ( NCT02453477 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6-76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10-1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome.
Keyphrases
- hematopoietic stem cell
- gene therapy
- sickle cell disease
- copy number
- bone marrow
- cardiac surgery
- induced apoptosis
- mitochondrial dna
- free survival
- cell cycle arrest
- cell therapy
- genome wide
- end stage renal disease
- newly diagnosed
- prognostic factors
- dna methylation
- acute kidney injury
- ejection fraction
- gene expression
- endoplasmic reticulum stress
- chronic kidney disease
- young adults
- case report
- signaling pathway
- stem cell transplantation
- high dose
- single cell
- cell death
- oxidative stress
- low dose
- combination therapy
- rectal cancer