Engineered U7 Small Nuclear RNA Restores Correct β-Globin Pre-mRNA Splicing in Mouse βiVS2-654-Thalassemic Erythroid Progenitor Cells

Annette D'Arqom; Tiwaporn Nualkaew; Natee Jearawiriyapaisarn; Ryszard Kole; Saovaros Svasti

doi:10.1089/hum.2020.145

Engineered U7 Small Nuclear RNA Restores Correct β-Globin Pre-mRNA Splicing in Mouse β^iVS2-654-Thalassemic Erythroid Progenitor Cells

Annette D'Arqom, Tiwaporn Nualkaew, Natee Jearawiriyapaisarn, Ryszard Kole, Saovaros Svasti

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Restoration of correct splicing of βIVS2-654-globin pre-mRNA was previously accomplished in erythroid cells from β-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 βIVS2-654 mutation. While correction of βIVS2-654 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.

Original language	English
Pages (from-to)	473-480
Number of pages	8
Journal	Human Gene Therapy
Volume	32
Issue number	9-10
DOIs	https://doi.org/10.1089/hum.2020.145
Publication status	Published - May 2021

Keywords

RNA splicing
U7 snRNA
thalassemia

Access to Document

10.1089/hum.2020.145

Cite this

@article{3d6742b852fc474aa51189c525321d0d,

title = "Engineered U7 Small Nuclear RNA Restores Correct β-Globin Pre-mRNA Splicing in Mouse βiVS2-654-Thalassemic Erythroid Progenitor Cells",

abstract = "Restoration of correct splicing of βIVS2-654-globin pre-mRNA was previously accomplished in erythroid cells from β-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 βIVS2-654 mutation. While correction of βIVS2-654 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.",

keywords = "RNA splicing, U7 snRNA, thalassemia",

author = "Annette D'Arqom and Tiwaporn Nualkaew and Natee Jearawiriyapaisarn and Ryszard Kole and Saovaros Svasti",

year = "2021",

month = may,

doi = "10.1089/hum.2020.145",

language = "English",

volume = "32",

pages = "473--480",

journal = "Human Gene Therapy",

issn = "1043-0342",

publisher = "Mary Ann Liebert Inc.",

number = "9-10",

}

TY - JOUR

T1 - Engineered U7 Small Nuclear RNA Restores Correct β-Globin Pre-mRNA Splicing in Mouse βiVS2-654-Thalassemic Erythroid Progenitor Cells

AU - D'Arqom, Annette

AU - Nualkaew, Tiwaporn

AU - Jearawiriyapaisarn, Natee

AU - Kole, Ryszard

AU - Svasti, Saovaros

PY - 2021/5

Y1 - 2021/5

N2 - Restoration of correct splicing of βIVS2-654-globin pre-mRNA was previously accomplished in erythroid cells from β-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 βIVS2-654 mutation. While correction of βIVS2-654 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.

AB - Restoration of correct splicing of βIVS2-654-globin pre-mRNA was previously accomplished in erythroid cells from β-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 βIVS2-654 mutation. While correction of βIVS2-654 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.

KW - RNA splicing

KW - U7 snRNA

KW - thalassemia

UR - http://www.scopus.com/inward/record.url?scp=85101504394&partnerID=8YFLogxK

U2 - 10.1089/hum.2020.145

DO - 10.1089/hum.2020.145

M3 - Article

C2 - 32977730

AN - SCOPUS:85101504394

SN - 1043-0342

VL - 32

SP - 473

EP - 480

JO - Human Gene Therapy

JF - Human Gene Therapy

IS - 9-10