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Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis

Authors :
Valentina Capo
Sara Penna
Ivan Merelli
Matteo Barcella
Serena Scala
Luca Basso-Ricci
Elena Draghici
Eleonora Palagano
Erika Zonari
Giacomo Desantis
Paolo Uva
Roberto Cusano
Lucia Sergi Sergi
Laura Crisafulli
Despina Moshous
Polina Stepensky
Katarzyna Drabko
Zühre Kaya
Ekrem Unal
Alper Gezdirici
Giuseppe Menna
Marta Serafini
Alessandro Aiuti
Silvia Laura Locatelli
Carmelo Carlo-Stella
Ansgar S. Schulz
Francesca Ficara
Cristina Sobacchi
Bernhard Gentner
Anna Villa
Source :
Haematologica, Vol 106, Iss 1 (2020)
Publication Year :
2020
Publisher :
Ferrata Storti Foundation, 2020.

Abstract

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, a relevant number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34+ cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34+ cells have a cellular composition that resembles bone marrow, supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPCs). To overcome the limit of bone marrow harvest/ HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex-vivo expansion of HSPCs coupled with lentiviral gene transfer. Circulating CD34+ cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector (LV) expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NSG recipients. Moreover, when CD34+ cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPCs coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by bone marrow fibrosis.

Details

Language :
English
ISSN :
03906078 and 15928721
Volume :
106
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Haematologica
Publication Type :
Academic Journal
Accession number :
edsdoj.41f41f3cd71f426da4e55083438ac158
Document Type :
article
Full Text :
https://doi.org/10.3324/haematol.2019.238261