Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II

Miles C. Smith; Lalitha R. Belur; Andrea D. Karlen; Kelly Podetz-Pedersen; Olivia Erlanson; Kanut Laoharawee; Justin Furcich; Troy C. Lund; Yun You; Davis Seelig; Beau R. Webber; R. Scott McIvor

doi:10.1016/j.ymgme.2023.107539

Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II

Miles C. Smith, Lalitha R. Belur, Andrea D. Karlen, Kelly Podetz-Pedersen, Olivia Erlanson, Kanut Laoharawee, Justin Furcich, Troy C. Lund, Yun You, Davis Seelig, Beau R. Webber, R. Scott McIvor

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

Abstract

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.

Original language	English (US)
Article number	107539
Journal	Molecular Genetics and Metabolism
Volume	138
Issue number	4
DOIs	https://doi.org/10.1016/j.ymgme.2023.107539
State	Published - Apr 2023

Bibliographical note

Funding 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.

Publisher Copyright:
© 2023

Keywords

CRISPR/Cas9
Glycosaminoglycans
Hunter syndrome
Iduronate-2-sulfatase
Mucopolysaccharidosis type II
NSG

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural

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Smith, M. C., Belur, L. R., Karlen, A. D., Podetz-Pedersen, K., Erlanson, O., Laoharawee, K., Furcich, J., Lund, T. C., You, Y., Seelig, D., Webber, B. R., & McIvor, R. S. (2023). Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II. Molecular Genetics and Metabolism, 138(4), Article 107539. https://doi.org/10.1016/j.ymgme.2023.107539

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title = "Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II",

abstract = "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.",

keywords = "CRISPR/Cas9, Glycosaminoglycans, Hunter syndrome, Iduronate-2-sulfatase, Mucopolysaccharidosis type II, NSG",

author = "Smith, {Miles C.} and Belur, {Lalitha R.} and Karlen, {Andrea D.} and Kelly Podetz-Pedersen and Olivia Erlanson and Kanut Laoharawee and Justin Furcich and Lund, {Troy C.} and Yun You and Davis Seelig and Webber, {Beau R.} and McIvor, {R. Scott}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2023",

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AU - Smith, Miles C.

AU - Belur, Lalitha R.

AU - Karlen, Andrea D.

AU - Podetz-Pedersen, Kelly

AU - Erlanson, Olivia

AU - Laoharawee, Kanut

AU - Furcich, Justin

AU - Lund, Troy C.

AU - You, Yun

AU - Seelig, Davis

AU - Webber, Beau R.

AU - McIvor, R. Scott

N1 - Funding 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. Publisher Copyright: © 2023

PY - 2023/4

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N2 - 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.

AB - 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.

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KW - Glycosaminoglycans

KW - Hunter syndrome

KW - Iduronate-2-sulfatase

KW - Mucopolysaccharidosis type II

KW - NSG

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VL - 138

JO - Molecular Genetics and Metabolism

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Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II

Abstract

Bibliographical note

Keywords

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