A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I

Daniel C. Mendez, Alexander E. Stover, Anthony D. Rangel, David J. Brick, Hubert E. Nethercott, Marissa A. Torres, Omar Khalid, Andrew MS Wong, Jonathan D. Cooper, James V. Jester, Edwin S. Monuki, Cian McGuire, Steven Q. Le, Shih hsin Kan, Patricia I. Dickson, Philip H. Schwartz

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Mucopolysaccharidosis type I (MPS I) is an inherited α-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-lived, providing a very narrow window to assess the long-term efficacy of therapeutic interventions. They also develop thymic lymphomas, making the assessment of potential tumorigenicity of human stem cell transplantation problematic. We therefore developed a new MPS I model based on a NOD/SCID/Il2rγ (NSG) background. This model lives longer than 1 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 were found to readily engraft, with human cells detectable for at least 1 year posttransplantation. This new MPS I model is thus suitable for preclinical testing of novel pluripotent stem cell-based therapy approaches.

Original languageEnglish
Pages (from-to)14068
Number of pages1
JournalMolecular Therapy - Methods and Clinical Development
StatePublished - Apr 29 2015


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