Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access

Autor: Fumagalli, Francesca, Calbi, Valeria, Natali Sora, Maria Grazia, Sessa, Maria, Baldoli, Cristina, Rancoita, Paola Maria V, Ciotti, Francesca, Sarzana, Marina, Fraschini, Maddalena, Zambon, Alberto Andrea, Acquati, Serena, Redaelli, Daniela, Attanasio, Vanessa, Miglietta, Simona, De Mattia, Fabiola, Barzaghi, Federica, Ferrua, Francesca, Migliavacca, Maddalena, Tucci, Francesca, Gallo, Vera, Del Carro, Ubaldo, Canale, Sabrina, Spiga, Ivana, Lorioli, Laura, Recupero, Salvatore, Fratini, Elena Sophia, Morena, Francesco, Silvani, Paolo, Calvi, Maria Rosa, Facchini, Marcella, Locatelli, Sara, Corti, Ambra, Zancan, Stefano, Antonioli, Gigliola, Farinelli, Giada, Gabaldo, Michela, Garcia-Segovia, Jesus, Schwab, Laetitia C, Downey, Gerald F, Filippi, Massimo, Cicalese, Maria Pia, Martino, Sabata, Di Serio, Clelia, Ciceri, Fabio, Bernardo, Maria Ester, Naldini, Luigi, Biffi, Alessandra, Aiuti, Alessandro
Přispěvatelé: Fumagalli, Francesca, Calbi, Valeria, Natali Sora, Maria Grazia, Sessa, Maria, Baldoli, Cristina, Rancoita, Paola Maria V, Ciotti, Francesca, Sarzana, Marina, Fraschini, Maddalena, Zambon, Alberto Andrea, Acquati, Serena, Redaelli, Daniela, Attanasio, Vanessa, Miglietta, Simona, De Mattia, Fabiola, Barzaghi, Federica, Ferrua, Francesca, Migliavacca, Maddalena, Tucci, Francesca, Gallo, Vera, Del Carro, Ubaldo, Canale, Sabrina, Spiga, Ivana, Lorioli, Laura, Recupero, Salvatore, Fratini, Elena Sophia, Morena, Francesco, Silvani, Paolo, Calvi, Maria Rosa, Facchini, Marcella, Locatelli, Sara, Corti, Ambra, Zancan, Stefano, Antonioli, Gigliola, Farinelli, Giada, Gabaldo, Michela, Garcia-Segovia, Jesu, Schwab, Laetitia C, Downey, Gerald F, Filippi, Massimo, Cicalese, Maria Pia, Martino, Sabata, Di Serio, Clelia, Ciceri, Fabio, Bernardo, Maria Ester, Naldini, Luigi, Biffi, Alessandra, Aiuti, Alessandro
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Lancet (London, England)
ISSN: 0156-0182
Popis: Summary Background Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD. Methods This study is an integrated analysis of results from a prospective, non-randomised, phase 1/2 clinical study and expanded-access frameworks. 29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel, a gene therapy containing an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA, and compared with an untreated natural history (NHx) cohort of 31 patients with early-onset MLD, matched by age and disease subtype. Patients were treated and followed up at Ospedale San Raffaele, Milan, Italy. The coprimary efficacy endpoints were an improvement of more than 10% in total gross motor function measure score at 2 years after treatment in treated patients compared with controls, and change from baseline of total peripheral blood mononuclear cell (PBMC) ARSA activity at 2 years after treatment compared with values before treatment. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01560182. Findings At the time of analyses, 26 patients treated with arsa-cel were alive with median follow-up of 3·16 years (range 0·64–7·51). Two patients died due to disease progression and one due to a sudden event deemed unlikely to be related to treatment. After busulfan conditioning, all arsa-cel treated patients showed sustained multilineage engraftment of genetically modified HSPCs. ARSA activity in PBMCs was significantly increased above baseline 2 years after treatment by a mean 18·7-fold (95% CI 8·3–42·2; p
Databáze: OpenAIRE
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