TY - JOUR
T1 - A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I
AU - Mendez, Daniel C.
AU - Stover, Alexander E.
AU - Rangel, Anthony D.
AU - Brick, David J.
AU - Nethercott, Hubert E.
AU - Torres, Marissa A.
AU - Khalid, Omar
AU - Wong, Andrew MS
AU - Cooper, Jonathan D.
AU - Jester, James V.
AU - Monuki, Edwin S.
AU - McGuire, Cian
AU - Le, Steven Q.
AU - Kan, Shih hsin
AU - Dickson, Patricia I.
AU - Schwartz, Philip H.
N1 - Publisher Copyright:
© 2015 American Society of Gene & Cell Therapy
PY - 2015/4/29
Y1 - 2015/4/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015229922&partnerID=8YFLogxK
U2 - 10.1038/mtm.2014.68
DO - 10.1038/mtm.2014.68
M3 - Article
C2 - 26052536
AN - SCOPUS:85015229922
SN - 2329-0501
VL - 2
SP - 14068
JO - Molecular Therapy - Methods and Clinical Development
JF - Molecular Therapy - Methods and Clinical Development
ER -