title: Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model.
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.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Visigalli
authors.forename: Stefania
authors.initials: S
authors.lastname: Delai
authors.forename: Letterio S
authors.initials: LS
authors.lastname: Politi
authors.forename: Carmela
authors.initials: C
authors.lastname: Di Domenico
authors.forename: Federica
authors.initials: F
authors.lastname: Cerri
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mrak
authors.forename: Raffaele
authors.initials: R
authors.lastname: D'Isa
authors.forename: Daniela
authors.initials: D
authors.lastname: Ungaro
authors.forename: Merel
authors.initials: M
authors.lastname: Stok
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mariani
authors.forename: Lidia
authors.initials: L
authors.lastname: Staszewsky
authors.forename: Claudia
authors.initials: C
authors.lastname: Godi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Russo
authors.forename: Francesca
authors.initials: F
authors.lastname: Cecere
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rubinacci
authors.forename: Riccardo
authors.initials: R
authors.lastname: Brambilla
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Paola
authors.initials: P
authors.lastname: Di Natale
authors.forename: Katherine
authors.initials: K
authors.lastname: Ponder
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Biffi
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007068:Iduronidase / Q000008:administration & dosage* / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D007068:Iduronidase