TY - JOUR
T1 - Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model
AU - Visigalli, Ilaria
AU - Delai, Stefania
AU - Politi, Letterio S.
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
PY - 2010/12/9
Y1 - 2010/12/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78449311112&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-04-278234
DO - 10.1182/blood-2010-04-278234
M3 - Article
C2 - 20847202
AN - SCOPUS:78449311112
SN - 0006-4971
VL - 116
SP - 5130
EP - 5139
JO - Blood
JF - Blood
IS - 24
ER -