Objectives: MLD is a fatal demyelinating lysosomal disease resulting from arylsulfatase A (ARSA) deficiency. Atidarsagene autotemcel (“arsa-cel”) is a haematopoietic stem and progenitor cell- based gene therapy consisting of autologous CD34+ cells transduced ex vivo with a lentiviral vector encoding for the human ARSA gene. Primary objectives were safety and efficacy of arsa-cel.
Methods: Thirty-eight patients with early-onset forms of MLD (20 late-infantile, 18 early-juvenile were treated with arsa-cel. Key endpoints were compared to an untreated natural history cohort.
Results: Of 38 patients treated, 35 are alive (2 died from disease progression, 1 from cerebral stroke, all unrelated to treatment). There were no treatment-related mortality or serious adverse events, no malignancies, no abnormal clonal expansion, and no evidence of replication-competent lentivirus. The majority of patients treated before symptom onset displayed long-term stabilisation of motor function, with many maintaining the ability to walk, and normal cognitive development.
Conclusions: Data from 38 early-onset MLD patients with up to 8.85 years of follow-up demonstrated that arsa-cel was generally well-tolerated and effective in modifying the disease course of early-onset MLD patients. Atidarsagene autotemcel (Libmeldy™) was approved by the European Medicines Agency in 2020 and is indicated for the treatment of children with late-infantile or early-juvenile forms, without clinical manifestations of the disease and in children with the early-juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Five European centres have been qualified to date to treat patients with arsa-cel.
Keywords: lysosomal, arsa, MLD
Francesca Fumagalli
IRCCS Ospedale San Raffaele
Italy
Valeria Calbi
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Alberto Zambon
IRCCS San Raffaele Scientific Institute
Italy
Vera Gallo
IRCCS San Raffaele Scientific Institute
Italy
Cristina Baldoli
IRCCS San Raffaele Scientific Institute
Italy
Federica Cugnata
Vita-Salute San Raffaele University
Italy
Paola M.V. Rancoita
IRCCS San Raffaele Scientific Institute
Italy
Fabiola De Mattia
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Elena Fratini
IRCCS San Raffaele Scientific Institute
Italy
Salvatore Recupero
IRCCS San Raffaele Scientific Institute
Italy
Francesca Ferrua
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Federica Barzaghi
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Maria Pia Cicalese
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Maddalena Migliavacca
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Francesca Tucci
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Francesca Ciotti
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Maddalena Fraschini
IRCCS San Raffaele Scientific Institute
Italy
Marina Sarzana
IRCCS San Raffaele Scientific Institute
Italy
Stefano Scarparo
IRCCS San Raffaele Scientific Institute
Italy
Paolo Silvani
IRCCS San Raffaele Scientific Institute
Italy
Sara Locatelli
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Alessandra Clerici
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Gigliola Antonioli
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Mara Sangalli
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Stefano Zancan
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET)
Italy
Andrea Calabria
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET)
Italy
Eugenio Montini
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET)
Italy
Giada Farinelli
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET)
Italy
Francesca Morena
University of Perugia
Italy
Jesus Segovia
Orchard Therapeutics (Europe) Limited
United Kingdom
Laetitia C. Schwab
Orchard Therapeutics (Europe) Limited
United Kingdom
Gerald Downey
Orchard Therapeutics (Europe) Limited
United Kingdom
Mirko M. Essing
Orchard Therapeutics (Europe) Limited
United Kingdom
Michela Gabaldo
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Sabata Martino
University of Perugia
Italy
Clelia Di Serio
Vita-Salute San Raffaele University
Italy
Fabio Ciceri
Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute
Italy
Massimo Filippi
Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute
Italy
Maria Sessa
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, ASST Papa Giovanni XXIII
Italy
Maria Grazia Natali Sora
IRCCS San Raffaele Scientific Institute
Italy
Maria Ester Bernardo
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Italy
Luigi Naldini
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University
Italy
Alessandra Biffi
Padua University and Hospital, Dana Farber/Boston Children’s Cancer and Blood Disorders Center
Italy
Alessandro Aiuti
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University
Italy
