Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model.
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.
Visigalli
Ilaria
I
San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Milan, Italy.
Delai
Stefania
S
Politi
Letterio S
LS
Di Domenico
Carmela
C
Cerri
Federica
F
Mrak
Emanuela
E
D'Isa
Raffaele
R
Ungaro
Daniela
D
Stok
Merel
M
Sanvito
Francesca
F
Mariani
Elisabetta
E
Staszewsky
Lidia
L
Godi
Claudia
C
Russo
Ilaria
I
Cecere
Francesca
F
Del Carro
Ubaldo
U
Rubinacci
Alessandro
A
Brambilla
Riccardo
R
Quattrini
Angelo
A
Di Natale
Paola
P
Ponder
Katherine
K
Naldini
Luigi
L
Biffi
Alessandra
A
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
D007068:Iduronidase