Abstract
Mucopolysaccharidosis type I (MPS I) is a metabolic disorder characterized by a deficiency in α-l-iduronidase (IDUA), leading to impaired glycosaminoglycan degradation. Current approved treatments seek to restore IDUA levels via enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). The effectiveness of these treatment strategies in preventing neurodegeneration is limited due to the inability of ERT to penetrate the blood-brain barrier (BBB) and HSCT's limited CNS reconstitution of IDUA levels. We reprogrammed human cord blood cells into induced pluripotent stem cells (iPSCs), differentiated them into human induced neural stem cells (hiNSCs), and sorted them using fluorescence-activated cell sorting (FACS). Our in vitro studies showed that these hiNSCs can migrate and cross-correct IDUA deficiency. Purified hiNSCs were then transplanted into neonatal immunodeficient MPS I mice (Idua -/- ). Analysis of brain tissue obtained 8 months after transplantation showed partially restored IDUA activity, with distribution and differentiation of engrafted hiNSCs throughout the brain into glial cell types. The presence of engrafted hiNSCs was associated with decreased levels of biomarkers commonly elevated in the Idua -/- mouse brain, such as β-hexosaminidase, CD68, and LAMP1, suggesting physiological efficacy. These results highlight the potential of hiNSCs for use as a patient-specific cellular therapy for MPS I.