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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2018
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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. |
format | Online Article Text |
id | pubmed-6080131 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
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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