602. Stem Cell Transplantation in a Novel, Long-Lived, and Highly Engraftable Immunodeficient Mouse Model of Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I (MPS I) is an inherited α-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multi-system organ dysfunction, neurological impairment, and death. We developed a new MPS I model based on a NOD/SCID/Il2rγ (NSG) background. This model lives longer than one year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells (HSCs) were found to readily engraft, with human cells detectable for at least one year post-transplantation. HSC transplantation at birth gave rise to improvement in behavioral parameters that lasted at least 3 months after transplantation. View Large Image | Download PowerPoint SlideBy 6 months, however, these effects were no longer present. Biochemical and cytometric analyses at 9 months after HSC transplantation showed that iduronidase activity in the liver and hexosaminidase activity in the brain were correlated with levels of HSC engraftment. Behavior at 9 months, however, was not correlated with levels of HSC engraftment suggesting that HSC engraftment, in and of itself, was insufficient to give a prolonged behavioral effect. Future studies will examine the effects of neural stem cells engraftment, with and without concomitant HSC engraftment.