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Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme rep...

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Autores principales: Laoharawee, Kanut, DeKelver, Russell C., Podetz-Pedersen, Kelly M., Rohde, Michelle, Sproul, Scott, Nguyen, Hoang-Oanh, Nguyen, Tam, St. Martin, Susan J., Ou, Li, Tom, Susan, Radeke, Robert, Meyer, Kathleen E., Holmes, Michael C., Whitley, Chester B., Wechsler, Thomas, McIvor, R. Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080131/
https://www.ncbi.nlm.nih.gov/pubmed/29580682
http://dx.doi.org/10.1016/j.ymthe.2018.03.002
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author Laoharawee, Kanut
DeKelver, Russell C.
Podetz-Pedersen, Kelly M.
Rohde, Michelle
Sproul, Scott
Nguyen, Hoang-Oanh
Nguyen, Tam
St. Martin, Susan J.
Ou, Li
Tom, Susan
Radeke, Robert
Meyer, Kathleen E.
Holmes, Michael C.
Whitley, Chester B.
Wechsler, Thomas
McIvor, R. Scott
author_facet Laoharawee, Kanut
DeKelver, Russell C.
Podetz-Pedersen, Kelly M.
Rohde, Michelle
Sproul, Scott
Nguyen, Hoang-Oanh
Nguyen, Tam
St. Martin, Susan J.
Ou, Li
Tom, Susan
Radeke, Robert
Meyer, Kathleen E.
Holmes, Michael C.
Whitley, Chester B.
Wechsler, Thomas
McIvor, R. Scott
author_sort Laoharawee, Kanut
collection PubMed
description Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme replacement therapy (ERT) requires lifelong infusions and does not provide neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to mediate genome editing for insertion of the human IDS (hIDS) coding sequence into a “safe harbor” site, intron 1 of the albumin locus in hepatocytes of an MPS II mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, we also demonstrate that ZFN-mediated genome editing prevented the development of neurocognitive deficit in young MPS II mice (6–9 weeks old) treated at high vector dose levels. We conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases.
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spelling pubmed-60801312019-04-04 Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing Laoharawee, Kanut DeKelver, Russell C. Podetz-Pedersen, Kelly M. Rohde, Michelle Sproul, Scott Nguyen, Hoang-Oanh Nguyen, Tam St. Martin, Susan J. Ou, Li Tom, Susan Radeke, Robert Meyer, Kathleen E. Holmes, Michael C. Whitley, Chester B. Wechsler, Thomas McIvor, R. Scott Mol Ther Original Article Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme replacement therapy (ERT) requires lifelong infusions and does not provide neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to mediate genome editing for insertion of the human IDS (hIDS) coding sequence into a “safe harbor” site, intron 1 of the albumin locus in hepatocytes of an MPS II mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, we also demonstrate that ZFN-mediated genome editing prevented the development of neurocognitive deficit in young MPS II mice (6–9 weeks old) treated at high vector dose levels. We conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases. American Society of Gene & Cell Therapy 2018-04-04 2018-03-10 /pmc/articles/PMC6080131/ /pubmed/29580682 http://dx.doi.org/10.1016/j.ymthe.2018.03.002 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Laoharawee, Kanut
DeKelver, Russell C.
Podetz-Pedersen, Kelly M.
Rohde, Michelle
Sproul, Scott
Nguyen, Hoang-Oanh
Nguyen, Tam
St. Martin, Susan J.
Ou, Li
Tom, Susan
Radeke, Robert
Meyer, Kathleen E.
Holmes, Michael C.
Whitley, Chester B.
Wechsler, Thomas
McIvor, R. Scott
Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing
title Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing
title_full Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing
title_fullStr Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing
title_full_unstemmed Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing
title_short Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing
title_sort dose-dependent prevention of metabolic and neurologic disease in murine mps ii by zfn-mediated in vivo genome editing
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080131/
https://www.ncbi.nlm.nih.gov/pubmed/29580682
http://dx.doi.org/10.1016/j.ymthe.2018.03.002
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