期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-17148-x
关键词
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资金
- Stanford's Child Health Research Institute (CHRI)
- Smart Family Parkison's disease Fund
- National Institute of Neurological Disorders and Stroke (NINDS) [P50 NS062684, 1K08NS102398-01]
Gaucher disease is a lysosomal storage disorder caused by insufficient glucocerebroside activity. Its hallmark manifestations are attributed to infiltration and inflammation by macrophages. Current therapies for Gaucher disease include life-long intravenous administration of recombinant glucocerebroside and orally-available glucosylceramide synthase inhibitors. An alternative approach is to engineer the patient's own hematopoietic system to restore glucocerebrosidase expression, thereby replacing the affected cells, and constituting a potential one-time therapy for this disease. Here, we report an efficient CRISPR/Cas9-based approach that targets glucocerebrosidase expression cassettes with a monocyte/macrophage-specific element to the CCR5 safe-harbor locus in human hematopoietic stem and progenitor cells. The targeted cells generate glucocerebroside-expressing macrophages and maintain long-term repopulation and multi-lineage differentiation potential with serial transplantation. The combination of a safe-harbor and a lineage-specific promoter establishes a universal correction strategy and circumvents potential toxicity of ectopic glucocerebrosidase in the stem cells. Furthermore, it constitutes an adaptable platform for other lysosomal enzyme deficiencies. Gaucher disease is a lysosomal storage disorder caused by insufficient glucocerebrosidase expression. Here, the authors describe a CRISPR/Cas9-based gene-editing approach to re-express this enzyme in human blood stem cells and show that they can engraft in NSG mice and differentiate into functional macrophages.
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