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 latter being present exclusively in the severe Hurler variant. The available treatments - enzyme replacement therapy and hematopoietic stem cell transplantation (HCT) - can ameliorate most disease manifestations, but their outcome on the skeletal and brain disease could be further improved. We here demonstrate that hematopoietic stem cell (HSC) gene therapy based on lentiviral vectors (LV) completely corrects the disease manifestations in the mouse model. Of note, the therapeutic benefit provided by gene therapy on critical MPS I manifestations, such as the neurological and skeletal disease, greatly exceeds the one exerted by HCT, the standard of care treatment for Hurler patients. Interestingly, therapeutic efficacy of HSC gene therapy is strictly dependent from the achievement of supra-normal enzyme activity in the hematopoietic system of transplanted mice, which allows enzyme delivery to the brain and skeleton for disease correction. Overall, our data provides evidence of an efficacious treatment for MPS I Hurler patients warranting future development towards clinical testing.