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, Matthew H. Porteus

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Article number4045
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Gomez-Ospina, N., Scharenberg, S. G., Mostrel, N., Bak, R. O., Mantri, S., Quadros, R. M., Gurumurthy, C. B., Lee, C., Bao, G., Suarez, C. J., Khan, S., Sawamoto, K., Tomatsu, S., Raj, N., Attardi, L. D., Aurelian, L., & Porteus, M. H. (2019). Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I. Nature communications, 10(1), [4045]. https://doi.org/10.1038/s41467-019-11962-8