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3. miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease

Author

Caserta, Carolina, Nucera, Silvia, Barcella, Matteo, Fazio, Grazia, Naldini, Matteo Maria, Pagani, Riccardo, Pavesi, Francesca, Desantis, Giacomo, Zonari, Erika, D’Angiò, Mariella, Capasso, Paola, Lombardo, Angelo, Merelli, Ivan, Spinelli, Orietta, Rambaldi, Alessandro, Ciceri, Fabio, Silvestri, Daniela, Valsecchi, Maria Grazia, Biondi, Andrea, Cazzaniga, Giovanni, and Gentner, Bernhard

Published
2023
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4. Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia

Author

Naldini, Matteo Maria, Casirati, Gabriele, Barcella, Matteo, Rancoita, Paola Maria Vittoria, Cosentino, Andrea, Caserta, Carolina, Pavesi, Francesca, Zonari, Erika, Desantis, Giacomo, Gilioli, Diego, Carrabba, Matteo Giovanni, Vago, Luca, Bernardi, Massimo, Di Micco, Raffaella, Di Serio, Clelia, Merelli, Ivan, Volpin, Monica, Montini, Eugenio, Ciceri, Fabio, and Gentner, Bernhard

Published
2023
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5. P1373: UNCOVERING UPSIDES AND PITFALLS OF BASE AND PRIME EDITING IN HEMATOPOIETIC STEM CELLS

Author

Fiumara, Martina, primary, Ferrari, Samuele, additional, Omer-Javed, Attya, additional, Beretta, Stefano, additional, Albano, Luisa, additional, Canarutto, Daniele, additional, Varesi, Angelica, additional, Gaddoni, Chiara, additional, Brombin, Chiara, additional, Cugnata, Federica, additional, Zonari, Erika, additional, Maria Naldini, Matteo, additional, Barcella, Matteo, additional, Gentner, Bernhard, additional, Merelli, Ivan, additional, and Naldini, Luigi, additional

Published
2023
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9. Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome

Author

Gentner, Bernhard, primary, Tucci, Francesca, additional, Galimberti, Stefania, additional, Fumagalli, Francesca, additional, De Pellegrin, Maurizio, additional, Silvani, Paolo, additional, Camesasca, Chiara, additional, Pontesilli, Silvia, additional, Darin, Silvia, additional, Ciotti, Francesca, additional, Sarzana, Marina, additional, Consiglieri, Giulia, additional, Filisetti, Chiara, additional, Forni, Giulia, additional, Passerini, Laura, additional, Tomasoni, Daniela, additional, Cesana, Daniela, additional, Calabria, Andrea, additional, Spinozzi, Giulio, additional, Cicalese, Maria-Pia, additional, Calbi, Valeria, additional, Migliavacca, Maddalena, additional, Barzaghi, Federica, additional, Ferrua, Francesca, additional, Gallo, Vera, additional, Miglietta, Simona, additional, Zonari, Erika, additional, Cheruku, Patali S., additional, Forni, Claudia, additional, Facchini, Marcella, additional, Corti, Ambra, additional, Gabaldo, Michela, additional, Zancan, Stefano, additional, Gasperini, Serena, additional, Rovelli, Attilio, additional, Boelens, Jaap-Jan, additional, Jones, Simon A., additional, Wynn, Robert, additional, Baldoli, Cristina, additional, Montini, Eugenio, additional, Gregori, Silvia, additional, Ciceri, Fabio, additional, Valsecchi, Maria G., additional, la Marca, Giancarlo, additional, Parini, Rossella, additional, Naldini, Luigi, additional, Aiuti, Alessandro, additional, and Bernardo, Maria-Ester, additional

Published
2021
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10. Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome

Author

Gentner, B, Tucci, F, Galimberti, S, Fumagalli, F, De Pellegrin, M, Silvani, P, Camesasca, C, Pontesilli, S, Darin, S, Ciotti, F, Sarzana, M, Consiglieri, G, Filisetti, C, Forni, G, Passerini, L, Tomasoni, D, Cesana, D, Calabria, A, Spinozzi, G, Cicalese, M, Calbi, V, Migliavacca, M, Barzaghi, F, Ferrua, F, Gallo, V, Miglietta, S, Zonari, E, Cheruku, P, Forni, C, Facchini, M, Corti, A, Gabaldo, M, Zancan, S, Gasperini, S, Rovelli, A, Boelens, J, Jones, S, Wynn, R, Baldoli, C, Montini, E, Gregori, S, Ciceri, F, Valsecchi, M, la Marca, G, Parini, R, Naldini, L, Aiuti, A, Bernardo, M, Gentner, Bernhard, Tucci, Francesca, Galimberti, Stefania, Fumagalli, Francesca, De Pellegrin, Maurizio, Silvani, Paolo, Camesasca, Chiara, Pontesilli, Silvia, Darin, Silvia, Ciotti, Francesca, Sarzana, Marina, Consiglieri, Giulia, Filisetti, Chiara, Forni, Giulia, Passerini, Laura, Tomasoni, Daniela, Cesana, Daniela, Calabria, Andrea, Spinozzi, Giulio, Cicalese, Maria-Pia, Calbi, Valeria, Migliavacca, Maddalena, Barzaghi, Federica, Ferrua, Francesca, Gallo, Vera, Miglietta, Simona, Zonari, Erika, Cheruku, Patali S, Forni, Claudia, Facchini, Marcella, Corti, Ambra, Gabaldo, Michela, Zancan, Stefano, Gasperini, Serena, Rovelli, Attilio, Boelens, Jaap-Jan, Jones, Simon A, Wynn, Robert, Baldoli, Cristina, Montini, Eugenio, Gregori, Silvia, Ciceri, Fabio, Valsecchi, Maria G, la Marca, Giancarlo, Parini, Rossella, Naldini, Luigi, Aiuti, Alessandro, Bernardo, Maria-Ester, Gentner, B, Tucci, F, Galimberti, S, Fumagalli, F, De Pellegrin, M, Silvani, P, Camesasca, C, Pontesilli, S, Darin, S, Ciotti, F, Sarzana, M, Consiglieri, G, Filisetti, C, Forni, G, Passerini, L, Tomasoni, D, Cesana, D, Calabria, A, Spinozzi, G, Cicalese, M, Calbi, V, Migliavacca, M, Barzaghi, F, Ferrua, F, Gallo, V, Miglietta, S, Zonari, E, Cheruku, P, Forni, C, Facchini, M, Corti, A, Gabaldo, M, Zancan, S, Gasperini, S, Rovelli, A, Boelens, J, Jones, S, Wynn, R, Baldoli, C, Montini, E, Gregori, S, Ciceri, F, Valsecchi, M, la Marca, G, Parini, R, Naldini, L, Aiuti, A, Bernardo, M, Gentner, Bernhard, Tucci, Francesca, Galimberti, Stefania, Fumagalli, Francesca, De Pellegrin, Maurizio, Silvani, Paolo, Camesasca, Chiara, Pontesilli, Silvia, Darin, Silvia, Ciotti, Francesca, Sarzana, Marina, Consiglieri, Giulia, Filisetti, Chiara, Forni, Giulia, Passerini, Laura, Tomasoni, Daniela, Cesana, Daniela, Calabria, Andrea, Spinozzi, Giulio, Cicalese, Maria-Pia, Calbi, Valeria, Migliavacca, Maddalena, Barzaghi, Federica, Ferrua, Francesca, Gallo, Vera, Miglietta, Simona, Zonari, Erika, Cheruku, Patali S, Forni, Claudia, Facchini, Marcella, Corti, Ambra, Gabaldo, Michela, Zancan, Stefano, Gasperini, Serena, Rovelli, Attilio, Boelens, Jaap-Jan, Jones, Simon A, Wynn, Robert, Baldoli, Cristina, Montini, Eugenio, Gregori, Silvia, Ciceri, Fabio, Valsecchi, Maria G, la Marca, Giancarlo, Parini, Rossella, Naldini, Luigi, Aiuti, Alessandro, and Bernardo, Maria-Ester

Abstract

Background Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. Methods We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an alpha-L-iduronidase (IDUA)-encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years. Results We now report interim results. The children's mean (+/- SD) age at the time of HSPC gene therapy was 1.9 +/- 0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced

Published
2021

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

Author

Capo, V, Penna, S, Merelli, I, Barcella, M, Scala, S, Basso-Ricci, L, Draghici, E, Palagano, E, Zonari, E, Desantis, G, Uva, P, Cusano, R, Sergi Sergi, L, Crisafulli, L, Moshous, D, Stepensky, P, Drabko, K, Kaya, Z, Unal, E, Gezdirici, A, Menna, G, Serafini, M, Aiuti, A, Locatelli, S, Carlo-Stella, C, Schulz, A, Ficara, F, Sobacchi, C, Gentner, B, Villa, A, Capo, Valentina, Penna, Sara, Merelli, Ivan, Barcella, Matteo, Scala, Serena, Basso-Ricci, Luca, Draghici, Elena, Palagano, Eleonora, Zonari, Erika, Desantis, Giacomo, Uva, Paolo, Cusano, Roberto, Sergi Sergi, Lucia, Crisafulli, Laura, Moshous, Despina, Stepensky, Polina, Drabko, Katarzyna, Kaya, Zühre, Unal, Ekrem, Gezdirici, Alper, Menna, Giuseppe, Serafini, Marta, Aiuti, Alessandro, Locatelli, Silvia Laura, Carlo-Stella, Carmelo, Schulz, Ansgar S, Ficara, Francesca, Sobacchi, Cristina, Gentner, Bernhard, Villa, Anna, Capo, V, Penna, S, Merelli, I, Barcella, M, Scala, S, Basso-Ricci, L, Draghici, E, Palagano, E, Zonari, E, Desantis, G, Uva, P, Cusano, R, Sergi Sergi, L, Crisafulli, L, Moshous, D, Stepensky, P, Drabko, K, Kaya, Z, Unal, E, Gezdirici, A, Menna, G, Serafini, M, Aiuti, A, Locatelli, S, Carlo-Stella, C, Schulz, A, Ficara, F, Sobacchi, C, Gentner, B, Villa, A, Capo, Valentina, Penna, Sara, Merelli, Ivan, Barcella, Matteo, Scala, Serena, Basso-Ricci, Luca, Draghici, Elena, Palagano, Eleonora, Zonari, Erika, Desantis, Giacomo, Uva, Paolo, Cusano, Roberto, Sergi Sergi, Lucia, Crisafulli, Laura, Moshous, Despina, Stepensky, Polina, Drabko, Katarzyna, Kaya, Zühre, Unal, Ekrem, Gezdirici, Alper, Menna, Giuseppe, Serafini, Marta, Aiuti, Alessandro, Locatelli, Silvia Laura, Carlo-Stella, Carmelo, Schulz, Ansgar S, Ficara, Francesca, Sobacchi, Cristina, Gentner, Bernhard, and Villa, Anna

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.

Published
2021

13. Ex vivo hematopoietic stem cell gene therapy for mucopolysaccharidosis type I (Hurler syndrome)

Author

Gentner, Bernhard, primary, Bernardo, Maria Ester, additional, Tucci, Francesca, additional, Fumagalli, Francesca, additional, Pontesilli, Silvia, additional, Silvani, Paolo, additional, Zonari, Erika, additional, Miglietta, Simona, additional, Montini, Eugenio, additional, Ciceri, Fabio, additional, La Marca, Giancarlo, additional, Parini, Rossella, additional, Naldini, Luigi, additional, and Aiuti, Alessandro, additional

Published
2021
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14. Exploitation of circulating CD34+ cells and non-genotoxic conditioning to overcome major limitations to treatment for autosomal recessive osteopetrosis

Author

Capo, Valentina, primary, Penna, Sara, additional, Merelli, Ivan, additional, Barcella, Matteo, additional, Scala, Serena, additional, Basso-Ricci, Luca, additional, Draghici, Elena, additional, Palagano, Eleonora, additional, Zonari, Erika, additional, Uva, Paolo, additional, Cusano, Roberto, additional, Aiuti, Alessandro, additional, Ficara, Francesca, additional, Sobacchi, Cristina, additional, Gentner, Bernhard, additional, and Villa, Anna, additional

Published
2020
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15. Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis

Author

Capo, Valentina, primary, Penna, Sara, additional, Merelli, Ivan, additional, Barcella, Matteo, additional, Scala, Serena, additional, Basso-Ricci, Luca, additional, Draghici, Elena, additional, Palagano, Eleonora, additional, Zonari, Erika, additional, Desantis, Giacomo, additional, Uva, Paolo, additional, Cusano, Roberto, additional, Sergi Sergi, Lucia, additional, Crisafulli, Laura, additional, Moshous, Despina, additional, Stepensky, Polina, additional, Drabko, Katarzyna, additional, Kaya, Zühre, additional, Unal, Ekrem, additional, Gezdirici, Alper, additional, Menna, Giuseppe, additional, Serafini, Marta, additional, Aiuti, Alessandro, additional, Locatelli, Silvia Laura, additional, Carlo-Stella, Carmelo, additional, Schulz, Ansgar S., additional, Ficara, Francesca, additional, Sobacchi, Cristina, additional, Gentner, Bernhard, additional, and Villa, Anna, additional

Published
2020
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16. Extensive Metabolic Correction of Hurler Disease By Hematopoietic Stem Cell-Based Gene Therapy: Preliminary Results from a Phase I/II Trial

Author

Gentner, Bernhard, primary, Bernardo, Maria Ester, primary, Tucci, Francesca, primary, Zonari, Erika, primary, Fumagalli, Francesca, primary, Pontesilli, Silvia, primary, Acquati, Serena, primary, Silvani, Paolo, primary, Ciceri, Fabio, primary, Rovelli, Attilio, primary, La Marca, Giancarlo, primary, Parini, Rossella, primary, Gregori, Silvia, primary, Montini, Eugenio, primary, Naldini, Luigi, primary, and Aiuti, Alessandro, primary

Published
2019
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18. Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy

Author

Zonari, Erika, primary, Desantis, Giacomo, additional, Petrillo, Carolina, additional, Boccalatte, Francesco E., additional, Lidonnici, Maria Rosa, additional, Kajaste-Rudnitski, Anna, additional, Aiuti, Alessandro, additional, Ferrari, Giuliana, additional, Naldini, Luigi, additional, and Gentner, Bernhard, additional

Published
2017
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19. Incremental Innovation of Ex Vivo Hematopoietic Stem Cell Engineering to Expand Clinical Gene Therapy Applications

Author

Zonari, Erika, primary, Desantis, Giacomo, additional, Petrillo, Carolina, additional, Meo, Oriana, additional, Scaramuzza, Samantha, additional, Lidonnici, Maria Rosa, additional, Kajaste-Rudnitski, Anna, additional, Ciceri, Fabio, additional, Marktel, Sarah, additional, Aiuti, Alessandro, additional, Ferrari, Giuliana, additional, Naldini, Luigi, additional, and Gentner, Bernhard, additional

Published
2016
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21. Tumor infiltrating myeloid cells: modulators of tumor microenvironment and novel therapeutic targets

Author

ZONARI, ERIKA and Zonari, E

Subjects
TAM, miR-155, tumor microenvironment, BIO/11 - BIOLOGIA MOLECOLARE
Abstract

Activation of a productive immune response requires transient upregulation of miR155 in the hematopoietic compartment. In order to investigate miR-155 in the context of tumor-associated immune responses, we stably knocked down (KD) miR-155 in the myeloid compartment of MMTV-PyMT mice (PyMT), a mouse model of spontaneous breast carcinogenesis that closely mimics tumor-host interactions seen in humans. Notably, myeloid cell specific miR-155 KD significantly accelerated tumor growth, as reflected by increased tumor mass and more pronounced secondary hematopoietic changes, i.e. leukocytosis and anemia. Mechanistically, miR155 KD reduces classical activation of tumor macrophages creating an imbalance towards a protumoral microenvironment as evidenced by up-regulation of the Th2 gene "IL13" in CD4+ T cells. Our studies are one of the first to implicate a miRNA in modulating myeloid responses in the tumor microenvironment. This study further highlights the importance of tumor infiltrating hematopoietic cells in fighting cancer development and establishes an antitumoral function of a prototypical oncomir, underscoring the context-specificity of miRNA regulation.

Published
2012

24. 288. Dual-Regulated Lentiviral Vector for Gene Therapy of X-Linked Chronic Granulomatous Disease

Author

Farinelli, Giada, primary, Chiriaco, Maria, additional, Capo, Valentina, additional, Zonari, Erika, additional, Migliavacca, Maddalena, additional, Jofra Hernandez, Raisa, additional, Scaramuzza, Samantha, additional, Di Matteo, Gigliola, additional, Sergi Sergi, Lucia, additional, Rossi, Alice, additional, Ranucci, Serena, additional, Bragonzi, Alessandra, additional, Kajaste-Rudnitski, Anna, additional, Trono, Didier, additional, Grez, Manuel, additional, Rossi, Paolo, additional, Finocchi, Andrea, additional, Naldini, Luigi, additional, Gentner, Bernhard, additional, and Aiuti, Alessandro, additional

Published
2015
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25. Dual-regulated Lentiviral Vector for Gene Therapy of X-linked Chronic Granulomatosis

Author

Chiriaco, Maria, primary, Farinelli, Giada, additional, Capo, Valentina, additional, Zonari, Erika, additional, Scaramuzza, Samantha, additional, Di Matteo, Gigliola, additional, Sergi, Lucia Sergi, additional, Migliavacca, Maddalena, additional, Hernandez, Raisa Jofra, additional, Bombelli, Ferdinando, additional, Giorda, Ezio, additional, Kajaste-Rudnitski, Anna, additional, Trono, Didier, additional, Grez, Manuel, additional, Rossi, Paolo, additional, Finocchi, Andrea, additional, Naldini, Luigi, additional, Gentner, Bernhard, additional, and Aiuti, Alessandro, additional

Published
2014
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26. Tumor infiltrating myeloid cells: modulators of tumor microenvironment and novel therapeutic targets

Author

NALDINI, LUIGI, Zonari, E, ZONARI, ERIKA, NALDINI, LUIGI, Zonari, E, and ZONARI, ERIKA

Abstract

Activation of a productive immune response requires transient upregulation of miR155 in the hematopoietic compartment. In order to investigate miR-155 in the context of tumor-associated immune responses, we stably knocked down (KD) miR-155 in the myeloid compartment of MMTV-PyMT mice (PyMT), a mouse model of spontaneous breast carcinogenesis that closely mimics tumor-host interactions seen in humans. Notably, myeloid cell specific miR-155 KD significantly accelerated tumor growth, as reflected by increased tumor mass and more pronounced secondary hematopoietic changes, i.e. leukocytosis and anemia. Mechanistically, miR155 KD reduces classical activation of tumor macrophages creating an imbalance towards a protumoral microenvironment as evidenced by up-regulation of the Th2 gene "IL13" in CD4+ T cells. Our studies are one of the first to implicate a miRNA in modulating myeloid responses in the tumor microenvironment. This study further highlights the importance of tumor infiltrating hematopoietic cells in fighting cancer development and establishes an antitumoral function of a prototypical oncomir, underscoring the context-specificity of miRNA regulation.

Published
2012

28. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis

Author

De Palma, Michele, Mazzieri, Roberta, Politi, Letterio S., Pucci, Ferdinando, Zonari, Erika, Sitia, Giovanni, Mazzoleni, Stefania, Moi, Davide, Venneri, Mary Anna, Indraccolo, Stefano, Falini, Andrea, Guidotti, Luca G., Galli, Rossella, and Naldini, Luigi

Subjects
Hematopoietic Stem Cell Transplantation, Cell Proliferation
Abstract

The use of type I interferons (IFNs) in cancer therapy has been limited by ineffective dosing and significant toxicity. Here, we exploited the tumor-homing ability of proangiogenic Tie2-expressing monocytes (TEMs) to deliver IFN-alpha to tumors. By transplanting hematopoietic progenitors transduced with a Tie2 promoter/enhancer-driven Ifna1 gene, we turned TEMs into IFN-alpha cell vehicles that efficiently targeted the IFN response to orthotopic human gliomas and spontaneous mouse mammary carcinomas and obtained significant antitumor responses and near complete abrogation of metastasis. TEM-mediated IFN-alpha delivery inhibited tumor angiogenesis and activated innate and adaptive immune cells but did not impair myelopoiesis and wound healing detectably. These results illustrate the therapeutic potential of gene- and cell-based IFN-alpha delivery and should allow the development of IFN treatments that more effectively treat cancer.

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

Author

Lucia Sergi Sergi, Polina Stepensky, Roberto Cusano, Serena Scala, Alper Gezdirici, Paolo Uva, Cristina Sobacchi, Bernhard Gentner, Eleonora Palagano, Ekrem Unal, Valentina Capo, Elena Draghici, Alessandro Aiuti, Ivan Merelli, Silvia L. Locatelli, Zühre Kaya, Carmelo Carlo-Stella, Ansgar Schulz, Laura Crisafulli, Luca Basso-Ricci, Francesca Ficara, Marta Serafini, Giacomo Desantis, Despina Moshous, Erika Zonari, Sara Penna, Giuseppe Menna, Matteo Barcella, Katarzyna Drabko, Anna Villa, Capo, V, Penna, S, Merelli, I, Barcella, M, Scala, S, Basso-Ricci, L, Draghici, E, Palagano, E, Zonari, E, Desantis, G, Uva, P, Cusano, R, Sergi Sergi, L, Crisafulli, L, Moshous, D, Stepensky, P, Drabko, K, Kaya, Z, Unal, E, Gezdirici, A, Menna, G, Serafini, M, Aiuti, A, Locatelli, S, Carlo-Stella, C, Schulz, A, Ficara, F, Sobacchi, C, Gentner, B, Villa, A, Capo, Valentina, Penna, Sara, Merelli, Ivan, Barcella, Matteo, Scala, Serena, Basso-Ricci, Luca, Draghici, Elena, Palagano, Eleonora, Zonari, Erika, Desantis, Giacomo, Uva, Paolo, Cusano, Roberto, Sergi Sergi, Lucia, Crisafulli, Laura, Moshous, Despina, Stepensky, Polina, Drabko, Katarzyna, Kaya, Zühre, Unal, Ekrem, Gezdirici, Alper, Menna, Giuseppe, Serafini, Marta, Aiuti, Alessandro, Locatelli, Silvia Laura, Carlo-Stella, Carmelo, Schulz, Ansgar S, Ficara, Francesca, Sobacchi, Cristina, Gentner, Bernhard, and Villa, Anna

Subjects
Vacuolar Proton-Translocating ATPases, Genetic enhancement, medicine.medical_treatment, CD34, Osteoclasts, Antigens, CD34, Hematopoietic stem cell transplantation, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Progenitor cell, 030304 developmental biology, 0303 health sciences, hematopoietic stem cell bone marrow failure stem cell transplantation Gene Therapy and Transfer HSPC expansion, Hematopoietic Stem Cell Transplantation, Hematopoietic stem cell, Hematopoietic Stem Cell, Genetic Therapy, Hematology, Hematopoietic Stem Cells, Bone Marrow Failure, HSPC expansion, Haematopoiesis, medicine.anatomical_structure, Gene Therapy and Transfer, Osteopetrosis, 030220 oncology & carcinogenesis, Cancer research, Bone marrow, Stem cell, Stem Cell Transplantation
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, an important 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 (BM), supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPC). To overcome the limit of BM harvest/HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex vivo expansion of HSPC coupled with lentiviral gene transfer. Circulating CD34(+). cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector 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 NOD scid gamma common chain (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 HSPC 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 BM fibrosis.

Published
2020

30. Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy

Author

Giuliana Ferrari, Luigi Naldini, Maria Rosa Lidonnici, Francesco Boccalatte, Erika Zonari, Anna Kajaste-Rudnitski, Bernhard Gentner, Giacomo Desantis, Alessandro Aiuti, Carolina Petrillo, Zonari, Erika, Desantis, Giacomo, Petrillo, Carolina, Boccalatte, Francesco E., Lidonnici, Maria Rosa, Kajaste Rudnitski, Anna, Aiuti, Alessandro, Ferrari, Giuliana, Naldini, Luigi, and Gentner, Bernhard

Subjects
0301 basic medicine, purified HSCs, HSC expansion, Genetic enhancement, Antigens, CD38, Cell Culture Techniques, CD34, Antigens, CD34, CD38, HSC gene therapy, Biochemistry, 0302 clinical medicine, Mice, Inbred NOD, Transduction, Genetic, lcsh:QH301-705.5, Cell Engineering, lcsh:R5-920, Hematopoietic Stem Cell Transplantation, Cell biology, Haematopoiesis, 030220 oncology & carcinogenesis, Genetic Vector, Stem cell, lcsh:Medicine (General), Cell Culture Technique, Human, Genetic Vectors, Biology, Article, Lentiviru, 03 medical and health sciences, Genetic, Genetics, Animals, Humans, Progenitor cell, Cell Proliferation, prostaglandin E2, Animal, Lentivirus, Hematopoietic Stem Cell, Genetic Therapy, Cell Biology, Hematopoietic Stem Cells, ADP-ribosyl Cyclase 1, Molecular biology, Transplantation, 030104 developmental biology, lcsh:Biology (General), UM171, lentiviral vector transduction, purified HSC, Ex vivo, Developmental Biology
Abstract

Summary Ex vivo gene therapy based on CD34+ hematopoietic stem cells (HSCs) has shown promising results in clinical trials, but genetic engineering to high levels and in large scale remains challenging. We devised a sorting strategy that captures more than 90% of HSC activity in less than 10% of mobilized peripheral blood (mPB) CD34+ cells, and modeled a transplantation protocol based on highly purified, genetically engineered HSCs co-infused with uncultured progenitor cells. Prostaglandin E2 stimulation allowed near-complete transduction of HSCs with lentiviral vectors during a culture time of less than 38 hr, mitigating the negative impact of standard culture on progenitor cell function. Exploiting the pyrimidoindole derivative UM171, we show that transduced mPB CD34+CD38− cells with repopulating potential could be expanded ex vivo. Implementing these findings in clinical gene therapy protocols will improve the efficacy, safety, and sustainability of gene therapy and generate new opportunities in the field of gene editing., Highlights • CD34+CD38− cells as an HSC-enriched starting population for ex vivo gene therapy • Reduced culture time (, In this article, Gentner and colleagues undertake a comprehensive strategy to advance ex vivo genetic engineering of HSCs for gene therapy. They experimentally define an optimal strategy to purify HSCs, which allows uncoupling long-term from short-term hematopoietic reconstitution, and implement ex vivo conditions that best preserve their biological properties applying novel transduction-enhancing compounds and pyrimidoindole derivatives to support HSC expansion.

Published
2017

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

Author

Capo V, Penna S, Merelli I, Barcella M, Scala S, Basso-Ricci L, Draghici E, Palagano E, Zonari E, Desantis G, Uva P, Cusano R, Sergi Sergi L, Crisafulli L, Moshous D, Stepensky P, Drabko K, Kaya Z, Unal E, Gezdirici A, Menna G, Serafini M, Aiuti A, Locatelli SL, Carlo-Stella C, Schulz AS, Ficara F, Sobacchi C, Gentner B, and Villa A

Subjects
Antigens, CD34, Genetic Therapy, Hematopoietic Stem Cells metabolism, Humans, Osteoclasts metabolism, Hematopoietic Stem Cell Transplantation, Osteopetrosis genetics, Osteopetrosis therapy, Vacuolar Proton-Translocating ATPases genetics, Vacuolar Proton-Translocating ATPases metabolism
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.

Published
2021
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