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

• Published in: Nature communications Vol. 10; no. 1; pp. 4045 - 14
• Main Authors: Gomez-Ospina, Natalia, Scharenberg, Samantha G., Mostrel, Nathalie, Bak, Rasmus O., Mantri, Sruthi, Quadros, Rolen M., Gurumurthy, Channabasavaiah B., Lee, Ciaran, Bao, Gang, Suarez, Carlos J., Khan, Shaukat, Sawamoto, Kazuki, Tomatsu, Shunji, Raj, Nitin, Attardi, Laura D., Aurelian, Laure, Porteus, Matthew H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 42/100; 42/41; 45/22; 45/29; 45/44; 49; 59; 631/208/2489/201/2110; 631/208/4041/3196; 64; 64/60; 82/51; 82/58; 96/31; Abnormalities; Animals; Antigens, CD34 - genetics; Antigens, CD34 - metabolism; CCR5 protein; CD34 antigen; CRISPR; CRISPR-Cas Systems; Disorders; Enzymes; Gene Editing - methods; Genetic disorders; Genetic Therapy - methods; Genome editing; Genome, Human; Genomes; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Hematopoietic system; Humanities and Social Sciences; Humans; Iduronidase - genetics; Iduronidase - metabolism; Lysosomal enzymes; Lysosomal storage diseases; Metabolic disorders; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mucopolysaccharidosis; Mucopolysaccharidosis I - genetics; Mucopolysaccharidosis I - pathology; Mucopolysaccharidosis I - therapy; multidisciplinary; NIH 3T3 Cells; Phenotype; Progenitor cells; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; Repopulation; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Therapeutic applications; Transplantation, Heterologous
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11962-8

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. Mucopolysaccharidosis type I (MPSI) is a lysosomal storage disease caused by insufficient iduronidase (IDUA) activity. Here, the authors use an ex vivo genome editing approach to overexpress IDUA in human hematopoietic stem and progenitor cells and show it can phenotypically correct MSPI in mouse model.