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Title: Enhancement of β-globin gene expression in thalassemic IVS2-654 induced pluripotent stem cell-derived erythroid cells by modified U7 snRNA
Authors: Phetcharat Phanthong
Suparerk Borwornpinyo
Narisorn Kitiyanant
Natee Jearawiriyapaisarn
Lalana Nuntakarn
Jirawat Saetan
Tiwaporn Nualkaew
Khanit Sa-Ngiamsuntorn
Usanarat Anurathapan
Andras Dinnyes
Yindee Kitiyanant
Suradej Hongeng
Mahidol University
Prince of Songkla University
BioTalentum Ltd.
Szent István Egyetem
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Apr-2017
Citation: Stem Cells Translational Medicine. Vol.6, No.4 (2017), 1059-1069
Abstract: © AlphaMed Press and 2017 The Authors. The therapeutic use of patient-specific induced pluripotent stem cells (iPSCs) is emerging as a potential treatment of b-thalassemia. Ideally, patient-specific iPSCs would be genetically corrected by various approaches to treat b-thalassemia including lentiviral gene transfer, lentivirus-delivered shRNA, and gene editing. These corrected iPSCs would be subsequently differentiated into hematopoietic stem cells and transplanted back into the same patient. In this article, we present a proof of principle study for disease modeling and screening using iPSCs to test the potential use of the modified U7 small nuclear (sn) RNA to correct a splice defect in IVS2-654 b-thalassemia. In this case, the aberration results from a mutation in the human b-globin intron 2 causing an aberrant splicing of b-globin pre-mRNA and preventing synthesis of functional b-globin protein. The iPSCs (derived from mesenchymal stromal cells from a patient with IVS2-654 b-thalassemia/hemoglobin (Hb) E) were transduced with a lentivirus carrying a modified U7 snRNA targeting an IVS2-654 b-globin pre-mRNA in order to restore the correct splicing. Erythroblasts differentiated from the transduced iPSCs expressed high level of correctly spliced b-globin mRNA suggesting that the modified U7 snRNA was expressed and mediated splicing correction of IVS2-654 b-globin pre-mRNA in these cells. Moreover, a less active apoptosis cascade process was observed in the corrected cells at transcription level. This study demonstrated the potential use of a genetically modified U7 snRNA with patient-specific iPSCs for the partial restoration of the aberrant splicing process of b-thalassemia.
ISSN: 21576580
Appears in Collections:Scopus 2016-2017

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