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

Natalia Gomez-Ospina (), Samantha G. Scharenberg, Nathalie Mostrel, Rasmus O. Bak, Sruthi Mantri, Rolen M. Quadros, Channabasavaiah B. Gurumurthy, Ciaran Lee, Gang Bao, Carlos J. Suarez, Shaukat Khan, Kazuki Sawamoto, Shunji Tomatsu, Nitin Raj, Laura D. Attardi, Laure Aurelian and Matthew H. Porteus ()
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Natalia Gomez-Ospina: Stanford University School of Medicine
Samantha G. Scharenberg: Stanford University School of Medicine
Nathalie Mostrel: Stanford University School of Medicine
Rasmus O. Bak: Aarhus University
Sruthi Mantri: Stanford University School of Medicine
Rolen M. Quadros: University of Nebraska Medical Center
Channabasavaiah B. Gurumurthy: University of Nebraska Medical Center
Ciaran Lee: Rice University
Gang Bao: Rice University
Carlos J. Suarez: Stanford University School of Medicine
Shaukat Khan: Nemours/ Alfred I. duPont Hospital for Children
Kazuki Sawamoto: Nemours/ Alfred I. duPont Hospital for Children
Shunji Tomatsu: Nemours/ Alfred I. duPont Hospital for Children
Nitin Raj: Stanford University School of Medicine
Laura D. Attardi: Stanford University School of Medicine
Laure Aurelian: Stanford University School of Medicine
Matthew H. Porteus: Stanford University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11962-8

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