Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy

Mayra F. Garcia-Rivera; Leah E. Colvin-Wanshura; Matthew S. Nelson; Zhenhong Nan; Shaukat A. Khan; Tyson B. Rogers; Indrani Maitra; Walter C. Low; Pankaj Gupta

doi:10.1016/j.brainresbull.2007.07.018

Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy

Mayra F. Garcia-Rivera, Leah E. Colvin-Wanshura, Matthew S. Nelson, Zhenhong Nan, Shaukat A. Khan, Tyson B. Rogers, Indrani Maitra, Walter C. Low, Pankaj Gupta

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Mucopolysaccharidosis type I (MPS-I or Hurler syndrome) is an inherited deficiency of the lysosomal glycosaminoglycan (GAG)-degrading enzyme α-l-iduronidase (IDUA) in which GAG accumulation causes progressive multi-system dysfunction and death. Early allogeneic hematopoietic stem cell transplantation (HSCT) ameliorates clinical features and extends life but is not available to all patients, and inadequately corrects its most devastating features including mental retardation and skeletal deformities. To test novel therapies, we characterized an immunodeficient MPS-I mouse model less likely to develop immune reactions to transplanted human or gene-corrected cells or secreted IDUA. In the liver, spleen, heart, lung, kidney and brain of NOD/SCID/MPS-I mice IDUA was undetectable, and reduced to half in heterozygotes. MPS-I mice developed marked GAG accumulation (3-38-fold) in these organs. Neuropathological examination showed GM₃ ganglioside accumulation in the striatum, cerebral peduncles, cerebellum and ventral brainstem of MPS-I mice. Urinary GAG excretion (6.5-fold higher in MPS-I mice) provided a non-invasive and reliable method suitable for serially following the biochemical efficacy of therapeutic interventions. We identified and validated using rigorous biostatistical methods, a highly reproducible method for evaluating sensorimotor function and motor skills development. This Rotarod test revealed marked abnormalities in sensorimotor integration involving the cerebellum, striatum, proprioceptive pathways, motor cortex, and in acquisition of motor coordination. NOD/SCID/MPS-I mice exhibit many of the clinical, skeletal, pathological and behavioral abnormalities of human MPS-I, and provide an extremely suitable animal model for assessing the systemic and neurological effects of human stem cell transplantation and gene therapeutic approaches, using the above techniques to measure efficacy.

Original language	English (US)
Pages (from-to)	429-438
Number of pages	10
Journal	Brain Research Bulletin
Volume	74
Issue number	6
DOIs	https://doi.org/10.1016/j.brainresbull.2007.07.018
State	Published - Nov 1 2007

Bibliographical note

Funding Information:
The authors thank Dr. Elizabeth F. Neufeld, Professor and Chair, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, for help and advice with the biochemical assays used in this work. This work was supported by NIH R01-NS-48606 (P.G. and W.C.L.), the US Department of Veterans Affairs (P.G.) and the Childrens Cancer Research Fund (P.G.).

Keywords

Animal model
Ganglioside
Glycosaminoglycans
Iduronidase
Mice
Mucopolysaccharidosis I
Rotarod performance test
Stem cell

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1016/j.brainresbull.2007.07.018

Find It

Find It at U of M Libraries

Cite this

Garcia-Rivera, M. F., Colvin-Wanshura, L. E., Nelson, M. S., Nan, Z., Khan, S. A., Rogers, T. B., Maitra, I., Low, W. C., & Gupta, P. (2007). Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy. Brain Research Bulletin, 74(6), 429-438. https://doi.org/10.1016/j.brainresbull.2007.07.018

Garcia-Rivera, MF, Colvin-Wanshura, LE, Nelson, MS, Nan, Z, Khan, SA, Rogers, TB, Maitra, I, Low, WC & Gupta, P 2007, 'Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy', Brain Research Bulletin, vol. 74, no. 6, pp. 429-438. https://doi.org/10.1016/j.brainresbull.2007.07.018

@article{474adb0c19454a909677833df1ad9eff,

title = "Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy",

abstract = "Mucopolysaccharidosis type I (MPS-I or Hurler syndrome) is an inherited deficiency of the lysosomal glycosaminoglycan (GAG)-degrading enzyme α-l-iduronidase (IDUA) in which GAG accumulation causes progressive multi-system dysfunction and death. Early allogeneic hematopoietic stem cell transplantation (HSCT) ameliorates clinical features and extends life but is not available to all patients, and inadequately corrects its most devastating features including mental retardation and skeletal deformities. To test novel therapies, we characterized an immunodeficient MPS-I mouse model less likely to develop immune reactions to transplanted human or gene-corrected cells or secreted IDUA. In the liver, spleen, heart, lung, kidney and brain of NOD/SCID/MPS-I mice IDUA was undetectable, and reduced to half in heterozygotes. MPS-I mice developed marked GAG accumulation (3-38-fold) in these organs. Neuropathological examination showed GM3 ganglioside accumulation in the striatum, cerebral peduncles, cerebellum and ventral brainstem of MPS-I mice. Urinary GAG excretion (6.5-fold higher in MPS-I mice) provided a non-invasive and reliable method suitable for serially following the biochemical efficacy of therapeutic interventions. We identified and validated using rigorous biostatistical methods, a highly reproducible method for evaluating sensorimotor function and motor skills development. This Rotarod test revealed marked abnormalities in sensorimotor integration involving the cerebellum, striatum, proprioceptive pathways, motor cortex, and in acquisition of motor coordination. NOD/SCID/MPS-I mice exhibit many of the clinical, skeletal, pathological and behavioral abnormalities of human MPS-I, and provide an extremely suitable animal model for assessing the systemic and neurological effects of human stem cell transplantation and gene therapeutic approaches, using the above techniques to measure efficacy.",

keywords = "Animal model, Ganglioside, Glycosaminoglycans, Iduronidase, Mice, Mucopolysaccharidosis I, Rotarod performance test, Stem cell",

author = "Garcia-Rivera, {Mayra F.} and Colvin-Wanshura, {Leah E.} and Nelson, {Matthew S.} and Zhenhong Nan and Khan, {Shaukat A.} and Rogers, {Tyson B.} and Indrani Maitra and Low, {Walter C.} and Pankaj Gupta",

note = "Funding Information: The authors thank Dr. Elizabeth F. Neufeld, Professor and Chair, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, for help and advice with the biochemical assays used in this work. This work was supported by NIH R01-NS-48606 (P.G. and W.C.L.), the US Department of Veterans Affairs (P.G.) and the Childrens Cancer Research Fund (P.G.).",

year = "2007",

month = nov,

day = "1",

doi = "10.1016/j.brainresbull.2007.07.018",

language = "English (US)",

volume = "74",

pages = "429--438",

journal = "Brain Research Bulletin",

issn = "0361-9230",

publisher = "Elsevier Inc.",

number = "6",

}

TY - JOUR

T1 - Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy

AU - Garcia-Rivera, Mayra F.

AU - Colvin-Wanshura, Leah E.

AU - Nelson, Matthew S.

AU - Nan, Zhenhong

AU - Khan, Shaukat A.

AU - Rogers, Tyson B.

AU - Maitra, Indrani

AU - Low, Walter C.

AU - Gupta, Pankaj

N1 - Funding Information: The authors thank Dr. Elizabeth F. Neufeld, Professor and Chair, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, for help and advice with the biochemical assays used in this work. This work was supported by NIH R01-NS-48606 (P.G. and W.C.L.), the US Department of Veterans Affairs (P.G.) and the Childrens Cancer Research Fund (P.G.).

PY - 2007/11/1

Y1 - 2007/11/1

N2 - Mucopolysaccharidosis type I (MPS-I or Hurler syndrome) is an inherited deficiency of the lysosomal glycosaminoglycan (GAG)-degrading enzyme α-l-iduronidase (IDUA) in which GAG accumulation causes progressive multi-system dysfunction and death. Early allogeneic hematopoietic stem cell transplantation (HSCT) ameliorates clinical features and extends life but is not available to all patients, and inadequately corrects its most devastating features including mental retardation and skeletal deformities. To test novel therapies, we characterized an immunodeficient MPS-I mouse model less likely to develop immune reactions to transplanted human or gene-corrected cells or secreted IDUA. In the liver, spleen, heart, lung, kidney and brain of NOD/SCID/MPS-I mice IDUA was undetectable, and reduced to half in heterozygotes. MPS-I mice developed marked GAG accumulation (3-38-fold) in these organs. Neuropathological examination showed GM3 ganglioside accumulation in the striatum, cerebral peduncles, cerebellum and ventral brainstem of MPS-I mice. Urinary GAG excretion (6.5-fold higher in MPS-I mice) provided a non-invasive and reliable method suitable for serially following the biochemical efficacy of therapeutic interventions. We identified and validated using rigorous biostatistical methods, a highly reproducible method for evaluating sensorimotor function and motor skills development. This Rotarod test revealed marked abnormalities in sensorimotor integration involving the cerebellum, striatum, proprioceptive pathways, motor cortex, and in acquisition of motor coordination. NOD/SCID/MPS-I mice exhibit many of the clinical, skeletal, pathological and behavioral abnormalities of human MPS-I, and provide an extremely suitable animal model for assessing the systemic and neurological effects of human stem cell transplantation and gene therapeutic approaches, using the above techniques to measure efficacy.

AB - Mucopolysaccharidosis type I (MPS-I or Hurler syndrome) is an inherited deficiency of the lysosomal glycosaminoglycan (GAG)-degrading enzyme α-l-iduronidase (IDUA) in which GAG accumulation causes progressive multi-system dysfunction and death. Early allogeneic hematopoietic stem cell transplantation (HSCT) ameliorates clinical features and extends life but is not available to all patients, and inadequately corrects its most devastating features including mental retardation and skeletal deformities. To test novel therapies, we characterized an immunodeficient MPS-I mouse model less likely to develop immune reactions to transplanted human or gene-corrected cells or secreted IDUA. In the liver, spleen, heart, lung, kidney and brain of NOD/SCID/MPS-I mice IDUA was undetectable, and reduced to half in heterozygotes. MPS-I mice developed marked GAG accumulation (3-38-fold) in these organs. Neuropathological examination showed GM3 ganglioside accumulation in the striatum, cerebral peduncles, cerebellum and ventral brainstem of MPS-I mice. Urinary GAG excretion (6.5-fold higher in MPS-I mice) provided a non-invasive and reliable method suitable for serially following the biochemical efficacy of therapeutic interventions. We identified and validated using rigorous biostatistical methods, a highly reproducible method for evaluating sensorimotor function and motor skills development. This Rotarod test revealed marked abnormalities in sensorimotor integration involving the cerebellum, striatum, proprioceptive pathways, motor cortex, and in acquisition of motor coordination. NOD/SCID/MPS-I mice exhibit many of the clinical, skeletal, pathological and behavioral abnormalities of human MPS-I, and provide an extremely suitable animal model for assessing the systemic and neurological effects of human stem cell transplantation and gene therapeutic approaches, using the above techniques to measure efficacy.

KW - Animal model

KW - Ganglioside

KW - Glycosaminoglycans

KW - Iduronidase

KW - Mice

KW - Mucopolysaccharidosis I

KW - Rotarod performance test

KW - Stem cell

UR - http://www.scopus.com/inward/record.url?scp=34848831191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34848831191&partnerID=8YFLogxK

U2 - 10.1016/j.brainresbull.2007.07.018

DO - 10.1016/j.brainresbull.2007.07.018

M3 - Article

C2 - 17920451

AN - SCOPUS:34848831191

SN - 0361-9230

VL - 74

SP - 429

EP - 438

JO - Brain Research Bulletin

JF - Brain Research Bulletin

IS - 6

ER -

Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this