Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing
| Autor: | Kanut Laoharawee, R. Scott McIvor, Hoang Oanh Nguyen, Michelle Rohde, Robert Radeke, Tam T Nguyen, Michael C. Holmes, Li Ou, Kelly M. Podetz-Pedersen, Scott Sproul, Thomas Wechsler, Russell Dekelver, Chester B. Whitley, Susan St Martin, Susan Tom, Kathleen Meyer |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
in vivo genome editing Genetic enhancement Gene Dosage Iduronate Sulfatase Pharmacology Biology law.invention Mice 03 medical and health sciences Genome editing law Drug Discovery Genetics medicine Animals Mucopolysaccharidosis type II Molecular Biology Mucopolysaccharidosis II Gene Editing lysosomal disease fungi Gene Transfer Techniques Iduronate-2-sulfatase Zinc Fingers Hunter syndrome Enzyme replacement therapy Endonucleases medicine.disease gene therapy Zinc finger nuclease zinc finger nuclease Introns Enzyme Activation Disease Models Animal Phenotype 030104 developmental biology MPS II albumin locus Hepatocytes Recombinant DNA Molecular Medicine Original Article Energy Metabolism Biomarkers iduronate 2-sulfatase |
| Zdroj: | Molecular Therapy |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2018.03.002 |
| Popis: | 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. AAV-mediated in vivo delivery of ZFN and IDS donor resulted in site-specific gene insertion and dose-dependent IDS expression in a mouse model of MPS II. These results support a currently open clinical trial, the first ever in vivo human genome editing study to be conducted. |
| Databáze: | OpenAIRE |
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