Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia

Sarah Marktel, Samantha Scaramuzza, Maria Pia Cicalese, Fabio Giglio, Stefania Galimberti, Maria Rosa Lidonnici, Valeria Calbi, Andrea Assanelli, Maria Ester Bernardo, Claudia Rossi, Andrea Calabria, Raffaella Milani, Salvatore Gattillo, Fabrizio Benedicenti, Giulio Spinozzi, Annamaria Aprile, Alessandra Bergami, Miriam Casiraghi, Giulia Consiglieri, Nicoletta Masera & 18 others Emanuela D’Angelo, Nadia Mirra, Raffaella Origa, Immacolata Tartaglione, Silverio Perrotta, Robert Winter, Milena Coppola, Gianluca Viarengo, Luca Santoleri, Giovanna Graziadei, Michela Gabaldo, Maria Grazia Valsecchi, Eugenio Montini, Luigi Naldini, Maria Domenica Cappellini, Fabio Ciceri, Alessandro Aiuti, Giuliana Ferrari

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalNature Medicine
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Gene therapy
Pediatrics
Thalassemia
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Stem cells
Genetic Therapy
Globins
Mutation
Hematopoietic Stem Cell Transplantation
Graft Rejection
Chelation
Life Expectancy
Grafts
Hemoglobins
Iron
Cell Count
Genes
Morbidity
Recovery

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia. / Marktel, Sarah; Scaramuzza, Samantha; Cicalese, Maria Pia; Giglio, Fabio; Galimberti, Stefania; Lidonnici, Maria Rosa; Calbi, Valeria; Assanelli, Andrea; Bernardo, Maria Ester; Rossi, Claudia; Calabria, Andrea; Milani, Raffaella; Gattillo, Salvatore; Benedicenti, Fabrizio; Spinozzi, Giulio; Aprile, Annamaria; Bergami, Alessandra; Casiraghi, Miriam; Consiglieri, Giulia; Masera, Nicoletta; D’Angelo, Emanuela; Mirra, Nadia; Origa, Raffaella; Tartaglione, Immacolata; Perrotta, Silverio; Winter, Robert; Coppola, Milena; Viarengo, Gianluca; Santoleri, Luca; Graziadei, Giovanna; Gabaldo, Michela; Valsecchi, Maria Grazia; Montini, Eugenio; Naldini, Luigi; Cappellini, Maria Domenica; Ciceri, Fabio; Aiuti, Alessandro; Ferrari, Giuliana.

In: Nature Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Marktel, Sarah ; Scaramuzza, Samantha ; Cicalese, Maria Pia ; Giglio, Fabio ; Galimberti, Stefania ; Lidonnici, Maria Rosa ; Calbi, Valeria ; Assanelli, Andrea ; Bernardo, Maria Ester ; Rossi, Claudia ; Calabria, Andrea ; Milani, Raffaella ; Gattillo, Salvatore ; Benedicenti, Fabrizio ; Spinozzi, Giulio ; Aprile, Annamaria ; Bergami, Alessandra ; Casiraghi, Miriam ; Consiglieri, Giulia ; Masera, Nicoletta ; D’Angelo, Emanuela ; Mirra, Nadia ; Origa, Raffaella ; Tartaglione, Immacolata ; Perrotta, Silverio ; Winter, Robert ; Coppola, Milena ; Viarengo, Gianluca ; Santoleri, Luca ; Graziadei, Giovanna ; Gabaldo, Michela ; Valsecchi, Maria Grazia ; Montini, Eugenio ; Naldini, Luigi ; Cappellini, Maria Domenica ; Ciceri, Fabio ; Aiuti, Alessandro ; Ferrari, Giuliana. / Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia. In: Nature Medicine. 2019.
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AU - Marktel, Sarah

AU - Scaramuzza, Samantha

AU - Cicalese, Maria Pia

AU - Giglio, Fabio

AU - Galimberti, Stefania

AU - Lidonnici, Maria Rosa

AU - Calbi, Valeria

AU - Assanelli, Andrea

AU - Bernardo, Maria Ester

AU - Rossi, Claudia

AU - Calabria, Andrea

AU - Milani, Raffaella

AU - Gattillo, Salvatore

AU - Benedicenti, Fabrizio

AU - Spinozzi, Giulio

AU - Aprile, Annamaria

AU - Bergami, Alessandra

AU - Casiraghi, Miriam

AU - Consiglieri, Giulia

AU - Masera, Nicoletta

AU - D’Angelo, Emanuela

AU - Mirra, Nadia

AU - Origa, Raffaella

AU - Tartaglione, Immacolata

AU - Perrotta, Silverio

AU - Winter, Robert

AU - Coppola, Milena

AU - Viarengo, Gianluca

AU - Santoleri, Luca

AU - Graziadei, Giovanna

AU - Gabaldo, Michela

AU - Valsecchi, Maria Grazia

AU - Montini, Eugenio

AU - Naldini, Luigi

AU - Cappellini, Maria Domenica

AU - Ciceri, Fabio

AU - Aiuti, Alessandro

AU - Ferrari, Giuliana

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