Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS−/− NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.
Bibliographical noteFunding Information:
Neurobehavioral studies were conducted at the Mouse Behavior Core at the University of Minnesota (supported by NIH grant NS062158 ). We thank core director Dr. Lind for help and advice with testing. The authors thank Sajya Singh and Tam Nguyen for their contributions to this work. Grant # 5T32GM113846 -10 Stem Cell Biology Training Program T32 at the University of Minnesota supported MCS during this work. R.S.M is an employee of and holds equity in Immusoft Corp. All other authors declare no competing interests.
- Hunter syndrome
- Mucopolysaccharidosis type II