ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome

Li Ou; Russell C. DeKelver; Michelle Rohde; Susan Tom; Robert Radeke; Susan J. St. Martin; Yolanda Santiago; Scott Sproul; Michelle J. Przybilla; Brenda L. Koniar; Kelly M. Podetz-Pedersen; Kanut Laoharawee; Renee D. Cooksley; Kathleen E. Meyer; Michael C. Holmes; R. Scott McIvor; Thomas Wechsler; Chester B. Whitley

doi:10.1016/j.ymthe.2018.10.018

ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome

Li Ou, Russell C. DeKelver, Michelle Rohde, Susan Tom, Robert Radeke, Susan J. St. Martin, Yolanda Santiago, Scott Sproul, Michelle J. Przybilla, Brenda L. Koniar, Kelly M. Podetz-Pedersen, Kanut Laoharawee, Renee D. Cooksley, Kathleen E. Meyer, Michael C. Holmes, R. Scott McIvor, Thomas Wechsler, Chester B. Whitley

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

70 Scopus citations

Abstract

Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases.

Original language	English (US)
Pages (from-to)	178-187
Number of pages	10
Journal	Molecular Therapy
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/j.ymthe.2018.10.018
State	Published - Jan 2 2019

Bibliographical note

Funding Information:
The authors would like to thank Carolyn Gaspar, Anne-Marie Ledeboer, Melanie Butler, and Amy Manning-Bog for assistance in necropsy and figure preparation, Seventh Wave Laboratories (Maryland Heights, MO) for performing necropsy and histopathology evaluation (Mark Martinez, DVM, DACVP), and Pacific BioLabs (Hercules, CA) for performing mass-spectrometry analysis of dermatan and heparan sulfate levels (Rick Staub and Vy Tran). This work was supported by Sangamo Therapeutics .

Funding Information:
The authors would like to thank Carolyn Gaspar, Anne-Marie Ledeboer, Melanie Butler, and Amy Manning-Bog for assistance in necropsy and figure preparation, Seventh Wave Laboratories (Maryland Heights, MO) for performing necropsy and histopathology evaluation (Mark Martinez, DVM, DACVP), and Pacific BioLabs (Hercules, CA) for performing mass-spectrometry analysis of dermatan and heparan sulfate levels (Rick Staub and Vy Tran). This work was supported by Sangamo Therapeutics.

Publisher Copyright:
© 2018 The Author(s)

Keywords

gene editing
gene therapy
lysosomal diseases
Zinc Finger Nucleases/genetics
Enzyme Replacement Therapy
Genetic Therapy/methods
Male
Mucopolysaccharidosis I/drug therapy
Gene Editing/methods
Lysosomal Storage Diseases/drug therapy
Animals
Female
Glycosaminoglycans/metabolism
Mice
Iduronidase/metabolism
Disease Models, Animal

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article

Publisher link

10.1016/j.ymthe.2018.10.018

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319315

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Ou, L., DeKelver, R. C., Rohde, M., Tom, S., Radeke, R., St. Martin, S. J., Santiago, Y., Sproul, S., Przybilla, M. J., Koniar, B. L., Podetz-Pedersen, K. M., Laoharawee, K., Cooksley, R. D., Meyer, K. E., Holmes, M. C., McIvor, R. S., Wechsler, T., & Whitley, C. B. (2019). ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome. Molecular Therapy, 27(1), 178-187. https://doi.org/10.1016/j.ymthe.2018.10.018

Ou, L, DeKelver, RC, Rohde, M, Tom, S, Radeke, R, St. Martin, SJ, Santiago, Y, Sproul, S, Przybilla, MJ, Koniar, BL, Podetz-Pedersen, KM, Laoharawee, K, Cooksley, RD, Meyer, KE, Holmes, MC, McIvor, RS, Wechsler, T & Whitley, CB 2019, 'ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome', Molecular Therapy, vol. 27, no. 1, pp. 178-187. https://doi.org/10.1016/j.ymthe.2018.10.018

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title = "ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome",

abstract = "Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases.",

keywords = "gene editing, gene therapy, lysosomal diseases, Zinc Finger Nucleases/genetics, Enzyme Replacement Therapy, Genetic Therapy/methods, Male, Mucopolysaccharidosis I/drug therapy, Gene Editing/methods, Lysosomal Storage Diseases/drug therapy, Animals, Female, Glycosaminoglycans/metabolism, Mice, Iduronidase/metabolism, Disease Models, Animal",

author = "Li Ou and DeKelver, \{Russell C.\} and Michelle Rohde and Susan Tom and Robert Radeke and \{St. Martin\}, \{Susan J.\} and Yolanda Santiago and Scott Sproul and Przybilla, \{Michelle J.\} and Koniar, \{Brenda L.\} and Podetz-Pedersen, \{Kelly M.\} and Kanut Laoharawee and Cooksley, \{Renee D.\} and Meyer, \{Kathleen E.\} and Holmes, \{Michael C.\} and McIvor, \{R. Scott\} and Thomas Wechsler and Whitley, \{Chester B.\}",

note = "Funding Information: The authors would like to thank Carolyn Gaspar, Anne-Marie Ledeboer, Melanie Butler, and Amy Manning-Bog for assistance in necropsy and figure preparation, Seventh Wave Laboratories (Maryland Heights, MO) for performing necropsy and histopathology evaluation (Mark Martinez, DVM, DACVP), and Pacific BioLabs (Hercules, CA) for performing mass-spectrometry analysis of dermatan and heparan sulfate levels (Rick Staub and Vy Tran). This work was supported by Sangamo Therapeutics . Funding Information: The authors would like to thank Carolyn Gaspar, Anne-Marie Ledeboer, Melanie Butler, and Amy Manning-Bog for assistance in necropsy and figure preparation, Seventh Wave Laboratories (Maryland Heights, MO) for performing necropsy and histopathology evaluation (Mark Martinez, DVM, DACVP), and Pacific BioLabs (Hercules, CA) for performing mass-spectrometry analysis of dermatan and heparan sulfate levels (Rick Staub and Vy Tran). This work was supported by Sangamo Therapeutics. Publisher Copyright: {\textcopyright} 2018 The Author(s)",

year = "2019",

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doi = "10.1016/j.ymthe.2018.10.018",

language = "English (US)",

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T1 - ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome

AU - Ou, Li

AU - DeKelver, Russell C.

AU - Rohde, Michelle

AU - Tom, Susan

AU - Radeke, Robert

AU - St. Martin, Susan J.

AU - Santiago, Yolanda

AU - Sproul, Scott

AU - Przybilla, Michelle J.

AU - Koniar, Brenda L.

AU - Podetz-Pedersen, Kelly M.

AU - Laoharawee, Kanut

AU - Cooksley, Renee D.

AU - Meyer, Kathleen E.

AU - Holmes, Michael C.

AU - McIvor, R. Scott

AU - Wechsler, Thomas

AU - Whitley, Chester B.

N1 - Funding Information: The authors would like to thank Carolyn Gaspar, Anne-Marie Ledeboer, Melanie Butler, and Amy Manning-Bog for assistance in necropsy and figure preparation, Seventh Wave Laboratories (Maryland Heights, MO) for performing necropsy and histopathology evaluation (Mark Martinez, DVM, DACVP), and Pacific BioLabs (Hercules, CA) for performing mass-spectrometry analysis of dermatan and heparan sulfate levels (Rick Staub and Vy Tran). This work was supported by Sangamo Therapeutics . Funding Information: The authors would like to thank Carolyn Gaspar, Anne-Marie Ledeboer, Melanie Butler, and Amy Manning-Bog for assistance in necropsy and figure preparation, Seventh Wave Laboratories (Maryland Heights, MO) for performing necropsy and histopathology evaluation (Mark Martinez, DVM, DACVP), and Pacific BioLabs (Hercules, CA) for performing mass-spectrometry analysis of dermatan and heparan sulfate levels (Rick Staub and Vy Tran). This work was supported by Sangamo Therapeutics. Publisher Copyright: © 2018 The Author(s)

PY - 2019/1/2

Y1 - 2019/1/2

N2 - Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases.

AB - Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases.

KW - gene editing

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KW - lysosomal diseases

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KW - Enzyme Replacement Therapy

KW - Genetic Therapy/methods

KW - Male

KW - Mucopolysaccharidosis I/drug therapy

KW - Gene Editing/methods

KW - Lysosomal Storage Diseases/drug therapy

KW - Animals

KW - Female

KW - Glycosaminoglycans/metabolism

KW - Mice

KW - Iduronidase/metabolism

KW - Disease Models, Animal

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SN - 1525-0016

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ER -

ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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