• Bernhard Gentner, Francesca Tucci, Stefania Galimberti, Francesca Fumagalli, Maurizio De Pellegrin, Paolo Silvani, Chiara Camesasca, Silvia Pontesilli, Silvia Darin, Francesca Ciotti, Marina Sarzana, Giulia Consiglieri, Chiara Filisetti, Giulia Forni, Laura Passerini, Daniela Tomasoni, Daniela Cesana, Andrea Calabria, Giulio Spinozzi, Maria-Pia Cicalese, Valeria Calbi, Maddalena Migliavacca, Federica Barzaghi, Francesca Ferrua, Vera Gallo, Simona Miglietta, Erika Zonari, Patali S Cheruku, Claudia Forni, Marcella Facchini, Ambra Corti, Michela Gabaldo, Stefano Zancan, Serena Gasperini, Attilio Rovelli, Jaap-Jan Boelens, Simon A Jones, Robert Wynn, Cristina Baldoli, Eugenio Montini, Silvia Gregori, Fabio Ciceri, Maria G Valsecchi, Giancarlo la Marca, Rossella Parini, Luigi Naldini, Alessandro Aiuti, Maria-Ester Bernardo, and MPSI Study Group.
• From the Departments of Hematology and Bone Marrow Transplantation (B.G., F. Ciceri), Pediatric Immunohematology and Bone Marrow Transplantation (F.T., F. Fumagalli, S.D., F. Ciotti, M.S., G.C., C. Filisetti, M.-P.C., V.C., M.M., F.B., F. Ferrua, V.G., A.A., M.-E.B.), Neurology and Neurophysiology (F. Fumagalli), Pediatric Orthopedics (M.D.P.), Anesthesia and Critical Care (P.S.), Pediatric Cardiology (C.C.), and Neuroradiology (S.P., C.B.) and the San Raffaele Telethon Institute for Gene Therapy (B.G., F.T., F. Fumagalli, L.P., D.T., D.C., A.C., G.S., M.-P.C., V.C., M.M., F.B., F. Ferrua, V.G., S.M., E.Z., P.S.C., M.F., A.C., E.M., S. Gregori, R.P., L.N., A.A., M.-E.B.), IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University (F. Ciceri, L.N., A.A., M.-E.B.), and Bicocca Bioinformatics, Biostatistics, and Bioimaging Center, School of Medicine and Surgery, University of Milano-Bicocca (S. Galimberti, M.G.V.), Milan, Fondazione Telethon, Rome (C. Forni, M.G., S.Z.), the Department of Experimental and Clinical Biomedical Sciences, University of Florence, and Newborn Screening, Biochemistry and Pharmacology Laboratory, Meyer Children's University Hospital (G.F., G.M.), Florence, and the Department of Pediatrics, Fondazione Monza e Brianza per il Bambino e la sua Mamma, San Gerardo Hospital, Monza (S. Gasperini, A.R., R.P.) - all in Italy; Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center, New York (J.-J.B.); and the Willink Unit, Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, University of Manchester (S.A.J.), and the Department of Blood and Marrow Transplantation, Royal Manchester Children's Hospital (R.W.) - both in Manchester, United Kingdom.
• N. Engl. J. Med. 2021 Nov 18; 385 (21): 1929-1940.

BackgroundAllogeneic 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.MethodsWe 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 α-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.ResultsWe 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 joint stiffness, and normal growth in line with World Health Organization growth charts.ConclusionsThe delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system. (Funded by Fondazione Telethon and others; ClinicalTrials.gov number, NCT03488394; EudraCT number, 2017-002430-23.).Copyright © 2021 Massachusetts Medical Society.

24 keywords...

hide…