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Your search keyword '"Canarutto, D."' showing total 4 results
Start Over Author "Canarutto, D." Publication Type Electronic Resources
4 results on '"Canarutto, D."'

1. Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency

Author

Castiello, M, Brandas, C, Ferrari, S, Porcellini, S, Sacchetti, N, Canarutto, D, Draghici, E, Merelli, I, Barcella, M, Pelosi, G, Vavassori, V, Varesi, A, Jacob, A, Scala, S, Basso Ricci, L, Paulis, M, Strina, D, Di Verniere, M, Sergi Sergi, L, Serafini, M, Holland, S, Bergerson, J, De Ravin, S, Malech, H, Pala, F, Bosticardo, M, Brombin, C, Cugnata, F, Calzoni, E, Crooks, G, Notarangelo, L, Genovese, P, Naldini, L, Villa, A, Castiello, Maria Carmina, Brandas, Chiara, Ferrari, Samuele, Porcellini, Simona, Sacchetti, Nicolò, Canarutto, Daniele, Draghici, Elena, Merelli, Ivan, Barcella, Matteo, Pelosi, Gabriele, Vavassori, Valentina, Varesi, Angelica, Jacob, Aurelien, Scala, Serena, Basso Ricci, Luca, Paulis, Marianna, Strina, Dario, Di Verniere, Martina, Sergi Sergi, Lucia, Serafini, Marta, Holland, Steven M., Bergerson, Jenna R. E., De Ravin, Suk See, Malech, Harry L., Pala, Francesca, Bosticardo, Marita, Brombin, Chiara, Cugnata, Federica, Calzoni, Enrica, Crooks, Gay M., Notarangelo, Luigi D., Genovese, Pietro, Naldini, Luigi, Villa, Anna, Castiello, M, Brandas, C, Ferrari, S, Porcellini, S, Sacchetti, N, Canarutto, D, Draghici, E, Merelli, I, Barcella, M, Pelosi, G, Vavassori, V, Varesi, A, Jacob, A, Scala, S, Basso Ricci, L, Paulis, M, Strina, D, Di Verniere, M, Sergi Sergi, L, Serafini, M, Holland, S, Bergerson, J, De Ravin, S, Malech, H, Pala, F, Bosticardo, M, Brombin, C, Cugnata, F, Calzoni, E, Crooks, G, Notarangelo, L, Genovese, P, Naldini, L, Villa, A, Castiello, Maria Carmina, Brandas, Chiara, Ferrari, Samuele, Porcellini, Simona, Sacchetti, Nicolò, Canarutto, Daniele, Draghici, Elena, Merelli, Ivan, Barcella, Matteo, Pelosi, Gabriele, Vavassori, Valentina, Varesi, Angelica, Jacob, Aurelien, Scala, Serena, Basso Ricci, Luca, Paulis, Marianna, Strina, Dario, Di Verniere, Martina, Sergi Sergi, Lucia, Serafini, Marta, Holland, Steven M., Bergerson, Jenna R. E., De Ravin, Suk See, Malech, Harry L., Pala, Francesca, Bosticardo, Marita, Brombin, Chiara, Cugnata, Federica, Calzoni, Enrica, Crooks, Gay M., Notarangelo, Luigi D., Genovese, Pietro, Naldini, Luigi, and Villa, Anna

Abstract

Recombination activating genes (RAGs) are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders. Hematopoietic stem and progenitor cell (HSPC) transplantation is the treatment of choice but is limited by donor availability and toxicity. To overcome these issues, we developed gene editing strategies targeting a corrective sequence into the human RAG1 gene by homology-directed repair (HDR) and validated them by tailored two-dimensional, three-dimensional, and in vivo xenotransplant platforms to assess rescue of expression and function. Whereas integration into intron 1 of RAG1 achieved suboptimal correction, in-frame insertion into exon 2 drove physiologic human RAG1 expression and activity, allowing disruption of the dominant-negative effects of unrepaired hypomorphic alleles. Enhanced HDR-mediated gene editing enabled the correction of human RAG1 in HSPCs from patients with hypomorphic RAG1 mutations to overcome T and B cell differentiation blocks. Gene correction efficiency exceeded the minimal proportion of functional HSPCs required to rescue immunodeficiency in Rag1(-/- )mice, supporting the clinical translation of HSPC gene editing for the treatment of RAG1 deficiency.

Published
2024

2. Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome

Author

Consiglieri, G, Tucci, F, De Pellegrin, M, Guerrini, B, Cattoni, A, Risca, G, Scarparo, S, Sarzana, M, Pontesilli, S, Mellone, R, Gasperini, S, Galimberti, S, Silvani, P, Filisetti, C, Darin, S, Forni, G, Miglietta, S, Santi, L, Facchini, M, Corti, A, Fumagalli, F, Cicalese, M, Calbi, V, Migliavacca, M, Barzaghi, F, Ferrua, F, Gallo, V, Recupero, S, Canarutto, D, Doglio, M, Tedesco, L, Volpi, N, Rovelli, A, la Marca, G, Valsecchi, M, Zancan, S, Ciceri, F, Naldini, L, Baldoli, C, Parini, R, Gentner, B, Aiuti, A, Bernardo, M, Consiglieri, Giulia, Tucci, Francesca, De Pellegrin, Maurizio, Guerrini, Barbara, Cattoni, Alessandro, Risca, Giulia, Scarparo, Stefano, Sarzana, Marina, Pontesilli, Silvia, Mellone, Renata, Gasperini, Serena, Galimberti, Stefania, Silvani, Paolo, Filisetti, Chiara, Darin, Silvia, Forni, Giulia, Miglietta, Simona, Santi, Ludovica, Facchini, Marcella, Corti, Ambra, Fumagalli, Francesca, Cicalese, Maria Pia, Calbi, Valeria, Migliavacca, Maddalena, Barzaghi, Federica, Ferrua, Francesca, Gallo, Vera, Recupero, Salvatore, Canarutto, Daniele, Doglio, Matteo, Tedesco, Lucia, Volpi, Nicola, Rovelli, Attilio, la Marca, Giancarlo, Valsecchi, Maria Grazia, Zancan, Stefano, Ciceri, Fabio, Naldini, Luigi, Baldoli, Cristina, Parini, Rossella, Gentner, Bernhard, Aiuti, Alessandro, Bernardo, Maria Ester, Consiglieri, G, Tucci, F, De Pellegrin, M, Guerrini, B, Cattoni, A, Risca, G, Scarparo, S, Sarzana, M, Pontesilli, S, Mellone, R, Gasperini, S, Galimberti, S, Silvani, P, Filisetti, C, Darin, S, Forni, G, Miglietta, S, Santi, L, Facchini, M, Corti, A, Fumagalli, F, Cicalese, M, Calbi, V, Migliavacca, M, Barzaghi, F, Ferrua, F, Gallo, V, Recupero, S, Canarutto, D, Doglio, M, Tedesco, L, Volpi, N, Rovelli, A, la Marca, G, Valsecchi, M, Zancan, S, Ciceri, F, Naldini, L, Baldoli, C, Parini, R, Gentner, B, Aiuti, A, Bernardo, M, Consiglieri, Giulia, Tucci, Francesca, De Pellegrin, Maurizio, Guerrini, Barbara, Cattoni, Alessandro, Risca, Giulia, Scarparo, Stefano, Sarzana, Marina, Pontesilli, Silvia, Mellone, Renata, Gasperini, Serena, Galimberti, Stefania, Silvani, Paolo, Filisetti, Chiara, Darin, Silvia, Forni, Giulia, Miglietta, Simona, Santi, Ludovica, Facchini, Marcella, Corti, Ambra, Fumagalli, Francesca, Cicalese, Maria Pia, Calbi, Valeria, Migliavacca, Maddalena, Barzaghi, Federica, Ferrua, Francesca, Gallo, Vera, Recupero, Salvatore, Canarutto, Daniele, Doglio, Matteo, Tedesco, Lucia, Volpi, Nicola, Rovelli, Attilio, la Marca, Giancarlo, Valsecchi, Maria Grazia, Zancan, Stefano, Ciceri, Fabio, Naldini, Luigi, Baldoli, Cristina, Parini, Rossella, Gentner, Bernhard, Aiuti, Alessandro, and Bernardo, Maria Ester

Abstract

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

Published
2024

3. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study

Author

Ferrua, F, Cicalese, M, Galimberti, S, Giannelli, S, Dionisio, F, Barzaghi, F, Migliavacca, M, Bernardo, M, Calbi, V, Assanelli, A, Facchini, M, Fossati, C, Albertazzi, E, Scaramuzza, S, Brigida, I, Scala, S, Basso-Ricci, L, Pajno, R, Casiraghi, M, Canarutto, D, Salerio, F, Albert, M, Bartoli, A, Wolf, H, Fiori, R, Silvani, P, Gattillo, S, Villa, A, Biasco, L, Dott, C, Culme-Seymour, E, van Rossem, K, Atkinson, G, Valsecchi, M, Roncarolo, M, Ciceri, F, Naldini, L, Aiuti, A, Cicalese, MP, Bernardo, ME, Assanelli, AA, Albert, MH, Wolf, HM, Fiori, Rossan, Culme-Seymour, EJ, Valsecchi, MG, Roncarolo, MG, Ferrua, F, Cicalese, M, Galimberti, S, Giannelli, S, Dionisio, F, Barzaghi, F, Migliavacca, M, Bernardo, M, Calbi, V, Assanelli, A, Facchini, M, Fossati, C, Albertazzi, E, Scaramuzza, S, Brigida, I, Scala, S, Basso-Ricci, L, Pajno, R, Casiraghi, M, Canarutto, D, Salerio, F, Albert, M, Bartoli, A, Wolf, H, Fiori, R, Silvani, P, Gattillo, S, Villa, A, Biasco, L, Dott, C, Culme-Seymour, E, van Rossem, K, Atkinson, G, Valsecchi, M, Roncarolo, M, Ciceri, F, Naldini, L, Aiuti, A, Cicalese, MP, Bernardo, ME, Assanelli, AA, Albert, MH, Wolf, HM, Fiori, Rossan, Culme-Seymour, EJ, Valsecchi, MG, and Roncarolo, MG

Abstract

Background: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC)gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. Methods: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP)expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462)and EudraCT (number 2009-017346-32). Findings: Between April 20, 2010, and Feb 26, 201

Published
2019

4. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study

Author

Ferrua, F, Cicalese, M, Galimberti, S, Giannelli, S, Dionisio, F, Barzaghi, F, Migliavacca, M, Bernardo, M, Calbi, V, Assanelli, A, Facchini, M, Fossati, C, Albertazzi, E, Scaramuzza, S, Brigida, I, Scala, S, Basso-Ricci, L, Pajno, R, Casiraghi, M, Canarutto, D, Salerio, F, Albert, M, Bartoli, A, Wolf, H, Fiori, R, Silvani, P, Gattillo, S, Villa, A, Biasco, L, Dott, C, Culme-Seymour, E, van Rossem, K, Atkinson, G, Valsecchi, M, Roncarolo, M, Ciceri, F, Naldini, L, Aiuti, A, Cicalese, MP, Bernardo, ME, Assanelli, AA, Albert, MH, Wolf, HM, Fiori, Rossan, Culme-Seymour, EJ, Valsecchi, MG, Roncarolo, MG, Ferrua, F, Cicalese, M, Galimberti, S, Giannelli, S, Dionisio, F, Barzaghi, F, Migliavacca, M, Bernardo, M, Calbi, V, Assanelli, A, Facchini, M, Fossati, C, Albertazzi, E, Scaramuzza, S, Brigida, I, Scala, S, Basso-Ricci, L, Pajno, R, Casiraghi, M, Canarutto, D, Salerio, F, Albert, M, Bartoli, A, Wolf, H, Fiori, R, Silvani, P, Gattillo, S, Villa, A, Biasco, L, Dott, C, Culme-Seymour, E, van Rossem, K, Atkinson, G, Valsecchi, M, Roncarolo, M, Ciceri, F, Naldini, L, Aiuti, A, Cicalese, MP, Bernardo, ME, Assanelli, AA, Albert, MH, Wolf, HM, Fiori, Rossan, Culme-Seymour, EJ, Valsecchi, MG, and Roncarolo, MG

Abstract

Background: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC)gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. Methods: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP)expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462)and EudraCT (number 2009-017346-32). Findings: Between April 20, 2010, and Feb 26, 201

Published
2019

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