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

Abstract

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.

Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I

“…We used CRISPR-Cas9 to knock-in the W392X mutation, analogous to the W402X mutation commonly found in patients with severe MPSI, into NSG mouse embryos (Supplementary Note 3). Homozygous NSG-IDUA X/X mice replicated the phenotype of patients affected with MPSI 1 and previously described immunocompetent 27,28 and immunocompromised 29 MPSI mice (Supplementary Figs. 6 and 7).…”

Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I

“…To determine the potential of human IDUA-HSPCs to correct the metabolic abnormalities of 194 MPSI, we established a new mouse model of the disease capable of engrafting human cells. NSG-195 IDUA X/X mice replicated the phenotype of patients affected with MPSI 1 and previously described 196 immunocompetent 19,20 and immunocompromised 21…”

Bioengineering an Artificial Human Blood–Brain Barrier in Rodents

“…One potential pitfall of creating a successfully perfused brain organoid model in NSG mice is the altered immunoreactivity of their central nervous system. Resident microglial cells in NSG mice show darker and more intense CD68 immunoreactivity than their WT counterparts [75]. Microglia have been shown to be involved in sealing a leaky blood–brain barrier [76].…”