Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Ilaria Visigalli, Stefania Delai, Letterio S. Politi, Carmela Di Domenico, Federica Cerri, Emanuela Mrak, Raffaele D'Isa, Daniela Ungaro, Merel Stok, Francesca Sanvito, Elisabetta Mariani, Lidia Staszewsky, Claudia Godi, Ilaria Russo, Francesca Cecere, Ubaldo Del Carro, Alessandro Rubinacci, Riccardo Brambilla, Angelo Quattrini, Paola Di NataleKatherine Ponder, Luigi Naldini, Alessandra Biffi

Research output: Contribution to journalArticle

Abstract

Type I mucopolysaccharidosis (MPS I) is a lysosomal storage disorder caused by the deficiency of α-L-iduronidase, which results in glycosaminoglycan accumulation in tissues. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation (the last being present exclusively in the severe Hurler variant). The available treatments, enzyme-replacement therapy and hematopoietic stem cell (HSC) transplantation, can ameliorate most disease manifestations, but their outcome on skeletal and brain disease could be further improved. We demonstrate here that HSC gene therapy, based on lentiviral vectors, completely corrects disease manifestations in the mouse model. Of note, the therapeutic benefit provided by gene therapy on critical MPS I manifestations, such as neurologic and skeletal disease, greatly exceeds that exerted by HSC transplantation, the standard of care treatment for Hurler patients. Interestingly, therapeutic efficacy of HSC gene therapy is strictly dependent on the achievement of supranormal enzyme activity in the hematopoietic system of transplanted mice, which allows enzyme delivery to the brain and skeleton for disease correction. Overall, our data provide evidence of an efficacious treatment for MPS I Hurler patients, warranting future development toward clinical testing.

Original languageEnglish
Pages (from-to)5130-5139
Number of pages10
JournalBlood
Volume116
Issue number24
DOIs
Publication statusPublished - Dec 9 2010

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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