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

95 Citations (Scopus)

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

Fingerprint

Mucopolysaccharidosis I
Gene therapy
Cell Transplantation
Genetic Therapy
Stem cells
Phenotype
Mucopolysaccharidoses
Hematopoietic Stem Cell Transplantation
Brain Diseases
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Brain
Iduronidase
Enzyme Replacement Therapy
Therapeutics
Hematopoietic System
Enzyme activity
Enzymes
Standard of Care
Glycosaminoglycans

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. / Visigalli, Ilaria; Delai, Stefania; Politi, Letterio S.; Di Domenico, Carmela; Cerri, Federica; Mrak, Emanuela; D'Isa, Raffaele; Ungaro, Daniela; Stok, Merel; Sanvito, Francesca; Mariani, Elisabetta; Staszewsky, Lidia; Godi, Claudia; Russo, Ilaria; Cecere, Francesca; Del Carro, Ubaldo; Rubinacci, Alessandro; Brambilla, Riccardo; Quattrini, Angelo; Di Natale, Paola; Ponder, Katherine; Naldini, Luigi; Biffi, Alessandra.

In: Blood, Vol. 116, No. 24, 09.12.2010, p. 5130-5139.

Research output: Contribution to journalArticle

Visigalli, I, Delai, S, Politi, LS, Di Domenico, C, Cerri, F, Mrak, E, D'Isa, R, Ungaro, D, Stok, M, Sanvito, F, Mariani, E, Staszewsky, L, Godi, C, Russo, I, Cecere, F, Del Carro, U, Rubinacci, A, Brambilla, R, Quattrini, A, Di Natale, P, Ponder, K, Naldini, L & Biffi, A 2010, 'Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model', Blood, vol. 116, no. 24, pp. 5130-5139. https://doi.org/10.1182/blood-2010-04-278234
Visigalli, Ilaria ; Delai, Stefania ; Politi, Letterio S. ; Di Domenico, Carmela ; Cerri, Federica ; Mrak, Emanuela ; D'Isa, Raffaele ; Ungaro, Daniela ; Stok, Merel ; Sanvito, Francesca ; Mariani, Elisabetta ; Staszewsky, Lidia ; Godi, Claudia ; Russo, Ilaria ; Cecere, Francesca ; Del Carro, Ubaldo ; Rubinacci, Alessandro ; Brambilla, Riccardo ; Quattrini, Angelo ; Di Natale, Paola ; Ponder, Katherine ; Naldini, Luigi ; Biffi, Alessandra. / Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. In: Blood. 2010 ; Vol. 116, No. 24. pp. 5130-5139.
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AU - Di Domenico, Carmela

AU - Cerri, Federica

AU - Mrak, Emanuela

AU - D'Isa, Raffaele

AU - Ungaro, Daniela

AU - Stok, Merel

AU - Sanvito, Francesca

AU - Mariani, Elisabetta

AU - Staszewsky, Lidia

AU - Godi, Claudia

AU - Russo, Ilaria

AU - Cecere, Francesca

AU - Del Carro, Ubaldo

AU - Rubinacci, Alessandro

AU - Brambilla, Riccardo

AU - Quattrini, Angelo

AU - Di Natale, Paola

AU - Ponder, Katherine

AU - Naldini, Luigi

AU - Biffi, Alessandra

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