Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Natalia Gomez-Ospina, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. gomezosp@stanford.edu.
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  • Samantha G Scharenberg, Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94035, USA.
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  • Nathalie Mostrel, Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94035, USA.
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  • Rasmus O Bak
  • Sruthi Mantri, Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94035, USA.
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  • Rolen M Quadros, Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office, University of Nebraska Medical Center, Omaha, NE, USA.
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  • Channabasavaiah B Gurumurthy, Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
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  • Ciaran Lee, Department of Bioengineering, Rice University, Houston, TX, USA.
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  • Gang Bao, Department of Bioengineering, Rice University, Houston, TX, USA.
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  • Carlos J Suarez, Department of Pathology and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
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  • Shaukat Khan, Nemours/ Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
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  • Kazuki Sawamoto, Nemours/ Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
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  • Shunji Tomatsu, Nemours/ Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
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  • Nitin Raj, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
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  • Laura D Attardi, Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
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  • Laure Aurelian, Department of Physiology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA. dbrag001@umaryland.edu
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  • Matthew H Porteus, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. mporteus@stanford.edu.

Lysosomal enzyme deficiencies comprise a large group of genetic disorders that generally lack effective treatments. A potential treatment approach is to engineer the patient's own hematopoietic system to express high levels of the deficient enzyme, thereby correcting the biochemical defect and halting disease progression. Here, we present an efficient ex vivo genome editing approach using CRISPR-Cas9 that targets the lysosomal enzyme iduronidase to the CCR5 safe harbor locus in human CD34+ hematopoietic stem and progenitor cells. The modified cells secrete supra-endogenous enzyme levels, maintain long-term repopulation and multi-lineage differentiation potential, and can improve biochemical and phenotypic abnormalities in an immunocompromised mouse model of Mucopolysaccharidosis type I. These studies provide support for the development of genome-edited CD34+ hematopoietic stem and progenitor cells as a potential treatment for Mucopolysaccharidosis type I. The safe harbor approach constitutes a flexible platform for the expression of lysosomal enzymes making it applicable to other lysosomal storage disorders.

Original languageEnglish
Article number4045
JournalNature Communications
Volume10
Issue1
Pages (from-to)4045
Number of pages14
ISSN2041-1723
DOIs
Publication statusPublished - 1 Dec 2019

    Research areas

  • CRISPR-CAS9, EFFICIENCY, GENE-THERAPY, GLOBIN GENE, HURLER-SYNDROME, LENTIVIRAL VECTOR, LYSOSOMAL-ENZYME, MURINE, PROTEIN, TRANSPLANTATION

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