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Engineering monocyte/macrophage-specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing.


ABSTRACT: 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.

SUBMITTER: Scharenberg SG 

PROVIDER: S-EPMC7335164 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Engineering monocyte/macrophage-specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing.

Scharenberg Samantha G SG   Poletto Edina E   Lucot Katherine L KL   Colella Pasqualina P   Sheikali Adam A   Montine Thomas J TJ   Porteus Matthew H MH   Gomez-Ospina Natalia N  

Nature communications 20200703 1


Gaucher disease is a lysosomal storage disorder caused by insufficient glucocerebrosidase activity. Its hallmark manifestations are attributed to infiltration and inflammation by macrophages. Current therapies for Gaucher disease include life-long intravenous administration of recombinant glucocerebrosidase and orally-available glucosylceramide synthase inhibitors. An alternative approach is to engineer the patient's own hematopoietic system to restore glucocerebrosidase expression, thereby repl  ...[more]

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