Journal
HUMAN GENE THERAPY
Volume 32, Issue 9-10, Pages 473-480Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2020.145
Keywords
thalassemia; U7 snRNA; RNA splicing
Categories
Funding
- National Research Council of Thailand (NRCT)
- Thailand Research Fund (TRF) [RSA6080086]
- Program Management Unit for Human Resources & Institutional Development, Research, and Innovation [B05F630062]
- Bilateral Programs, Japan Society for the Promotion of Science (JSPS)
- Mahidol University [MRC-MGR 01/2563]
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Restoration of correct splicing of beta(IVS2-654)-globin pre-mRNA was successfully achieved in thalassemic mice using engineered U7.BP+623 snRNA, but a high level of truncated U7.BP+623 snRNA was also observed. Differences in the processing of modified U7 snRNA between human and mouse constructs hindered the evaluation of pathological improvement in the mouse model.
Restoration of correct splicing of beta(IVS2-654)-globin pre-mRNA was previously accomplished in erythroid cells from beta-thalassemia/HbE patients by an engineered U7 small nuclear RNA (snRNA) that carried a sequence targeted to the cryptic branch point and an exonic splicing enhancer, U7.BP+623 snRNA. In this study, this approach was tested in thalassemic mice carrying the beta(IVS2-654) mutation. While correction of beta(IVS2-654) pre-mRNA splicing was achieved in erythroid progenitors transduced with a lentiviral vector carrying the U7.BP+623 snRNA, a high level of truncated U7.BP+623 snRNA was also observed. The discrepancy of processing of the modified U7 snRNA in human and mouse constructs hamper the evaluation of pathologic improvement in mouse model.
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