Background: Allogeneic 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. 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 á-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 genecorrected 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.

Hematopoietic stem-and progenitor-cell gene therapy for hurler syndrome / Gentner, B.; Tucci, F.; Galimberti, S.; Fumagalli, F.; De Pellegrin, M.; Silvani, P.; Camesasca, C.; Pontesilli, S.; Darin, S.; Ciotti, F.; Sarzana, M.; Consiglieri, G.; Filisetti, C.; Forni, G.; Passerini, L.; Tomasoni, D.; Cesana, D.; Calabria, A.; Spinozzi, G.; Cicalese, M. -P.; Calbi, V.; Migliavacca, M.; Barzaghi, F.; Ferrua, F.; Gallo, V.; Miglietta, S.; Zonari, E.; Cheruku, P. S.; Forni, C.; Facchini, M.; Corti, A.; Gabaldo, M.; Zancan, S.; Gasperini, S.; Rovelli, A.; Boelens, J. -J.; Jones, S. A.; Wynn, R.; Baldoli, C.; Montini, E.; Gregori, S.; Ciceri, F.; Valsecchi, M. G.; La Marca, G.; Parini, R.; Naldini, L.; Aiuti, A.; Bernardo, M. -E.. - In: THE NEW ENGLAND JOURNAL OF MEDICINE. - ISSN 0028-4793. - 385:21(2021), pp. 1929-1940. [10.1056/NEJMoa2106596]

Hematopoietic stem-and progenitor-cell gene therapy for hurler syndrome

Consiglieri G.;Filisetti C.;Cicalese M. -P.;Ferrua F.;Corti A.;Ciceri F.;Naldini L.;Aiuti A.
Penultimo
;
Bernardo M. -E.
Ultimo
2021-01-01

Abstract

Background: Allogeneic 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. 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 á-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 genecorrected 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.
2021
Child, Preschool
Female
Follow-Up Studies
Genetic Vectors
Glycosaminoglycans
Humans
Iduronidase
Infant
Lentivirus
Male
Mucopolysaccharidosis I
Mutation
Stem Cell Transplantation
Transplantation, Autologous
Genetic Therapy
Hematopoietic Stem Cell Transplantation
File in questo prodotto:
File Dimensione Formato  
Gentner_NEJM_2021.pdf

solo gestori archivio

Tipologia: PDF editoriale (versione pubblicata dall'editore)
Licenza: Copyright dell'editore
Dimensione 1.08 MB
Formato Adobe PDF
1.08 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/125018
Citazioni
  • ???jsp.display-item.citation.pmc??? 45
  • Scopus 81
  • ???jsp.display-item.citation.isi??? 76
social impact