Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome.
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Gentner Bernhard, Tucci Francesca, Galimberti Stefania, Fumagalli Francesca, De Pellegrin Maurizio, Silvani Paolo, Camesasca Chiara, Pontesilli Silvia, Darin Silvia, Ciotti Francesca, Sarzana Marina, Consiglieri Giulia, Filisetti Chiara, Forni Giulia, Passerini Laura, Tomasoni Daniela, Cesana Daniela, Calabria Andrea, Spinozzi Giulio, Cicalese Maria-Pia, Calbi Valeria, Migliavacca Maddalena, Barzaghi Federica, Ferrua Francesca, Gallo Vera, Miglietta Simona, Zonari Erika, Cheruku Patali S, Forni Claudia, Facchini Marcella, Corti Ambra, Gabaldo Michela, Zancan Stefano, Gasperini Serena, Rovelli Attilio, Boelens Jaap-Jan, Jones Simon A, Wynn Robert, Baldoli Cristina, Montini Eugenio, Gregori Silvia, Ciceri Fabio, Valsecchi Maria G, la Marca Giancarlo, Parini Rossella, Naldini Luigi, Aiuti Alessandro, Bernardo Maria-Ester, MPSI Study Group
Аннотация
METHODS: We 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.
RESULTS: We 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.
CONCLUSIONS: The 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.).