• Francesca Fumagalli, Valeria Calbi, Natali SoraMaria GraziaMGUnits of Neurology and Neurophysiology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Maria Sessa, Cristina Baldoli, Paola Maria V Rancoita, Francesca Ciotti, Marina Sarzana, Maddalena Fraschini, Alberto Andrea Zambon, Serena Acquati, Daniela Redaelli, Vanessa Attanasio, Simona Miglietta, Fabiola De Mattia, Federica Barzaghi, Francesca Ferrua, Maddalena Migliavacca, Francesca Tucci, Vera Gallo, Ubaldo Del Carro, Sabrina Canale, Ivana Spiga, Laura Lorioli, Salvatore Recupero, Elena Sophia Fratini, Francesco Morena, Paolo Silvani, Maria Rosa Calvi, Marcella Facchini, Sara Locatelli, Ambra Corti, Stefano Zancan, Gigliola Antonioli, Giada Farinelli, Michela Gabaldo, Jesus Garcia-Segovia, Laetitia C Schwab, Gerald F Downey, Massimo Filippi, Maria Pia Cicalese, Sabata Martino, Clelia Di Serio, Fabio Ciceri, Maria Ester Bernardo, Luigi Naldini, Alessandra Biffi, and Alessandro Aiuti.
• San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy; Units of Neurology and Neurophysiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
• Lancet. 2022 Jan 22; 399 (10322): 372-383.

BackgroundEffective 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.MethodsThis 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.FindingsAt 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<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6-12·4; p<0·0001) in patients with the early-juvenile variant. Mean differences in total scores for gross motor function measure between treated patients and age-matched and disease subtype-matched NHx patients 2 years after treatment were significant for both patients with late-infantile MLD (66% [95% CI 48·9-82·3]) and early-juvenile MLD (42% [12·3-71·8]). Most treated patients progressively acquired motor skills within the predicted range of healthy children or had stabilised motor performance (maintaining the ability to walk). Further, most displayed normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up; treatment benefits were particularly apparent in patients treated before symptom onset. The infusion was well tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus. All patients had at least one grade 3 or higher adverse event; most were related to conditioning or to background disease. The only adverse event related to arsa-cel was the transient development of anti-ARSA antibodies in four patients, which did not affect clinical outcomes.InterpretationTreatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy.FundingOrchard Therapeutics, Fondazione Telethon, and GlaxoSmithKline.Copyright © 2022 Elsevier Ltd. All rights reserved.

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