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 multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-liv...

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Bibliographic Details
Published in:	Molecular therapy. Methods & clinical development Vol. 2; p. 14068
Main Authors:	Mendez, Daniel C, Stover, Alexander E, Rangel, Anthony D, Brick, David J, Nethercott, Hubert E, Torres, Marissa A, Khalid, Omar, Wong, Andrew Ms, Cooper, Jonathan D, Jester, James V, Monuki, Edwin S, McGuire, Cian, Le, Steven Q, Kan, Shih-Hsin, Dickson, Patricia I, Schwartz, Philip H
Format:	Journal Article
Language:	English
Published:	United States Elsevier Limited 01-01-2015 Nature Publishing Group Elsevier
Online Access:	Get full text
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The first four authors contributed equally to this work.
ISSN:	2329-0501 2329-0501
DOI:	10.1038/mtm.2014.68