RNA repair restores hemoglobin expression in IVS2-654 thalassemic mice

被引：64

作者：

Svasti, Saovaros ^{[2
,3
]}

Suwanmanee, Thipparat ^{[2
]}

Fucharoen, Suthat ^{[3
]}

Moulton, Hong M. ^{[4
]}

Nelson, Michelle H. ^{[4
]}

Maeda, Nobuyo ^{[1
]}

Smithies, Oliver ^{[1
]}

Kole, Ryszard ^{[2
,4
]}

机构：

[1] Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Dept Pharmacol, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[3] Mahidol Univ, Thalassemia Res Ctr, Inst Sci & Technol Res & Dev, Nakhon Pathom 73170, Thailand

[4] AVI BioPharma, Corvallis, OR 97333 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 04期

基金：

美国国家卫生研究院;

关键词：

oligonucleotides; RNA splicing; thalassemia; therapy; morpholino oligomers; ANTISENSE OLIGONUCLEOTIDES; ERYTHROID-CELLS; GENE-EXPRESSION; BETA-THALASSEMIA; MESSENGER-RNA; RESTORATION; DELIVERY; MUTATION;

D O I：

10.1073/pnas.0812436106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Repair of beta-globin pre-mRNA rendered defective by a thalassemia-causing splicing mutation, IVS2-654, in intron 2 of the human beta-globin gene was accomplished in vivo in a mouse model of IVS2-654 thalassemia. This was effected by a systemically delivered splice-switching oligonucleotide (SSO), a morpholino oligomer conjugated to an arginine-rich peptide. The SSO blocked the aberrant splice site in the targeted pre-mRNA and forced the splicing machinery to reselect existing correct splice sites. Repaired beta-globin mRNA restored significant amounts of hemoglobin in the peripheral blood of the IVS2-654 mouse, improving the number and quality of erythroid cells.

引用

页码：1205 / 1210

页数：6

共 29 条

[1] Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology [J].

Alter, J ;

Lou, F ;

Rabinowitz, A ;

Yin, HF ;

Rosenfeld, J ;

Wilton, SD ;

Partridge, TA ;

Lu, QL .

NATURE MEDICINE, 2006, 12 (02) :175-177

[2] Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing [J].

Chao, HJ ;

Mansfield, SG ;

Bartel, RC ;

Hiriyanna, S ;

Mitchell, LG ;

Garcia-Blanco, M ;

Walsh, CE .

NATURE MEDICINE, 2003, 9 (08) :1015-1019

[3] BETA-THALASSEMIA IN CHINESE - USE OF INVIVO RNA ANALYSIS AND OLIGONUCLEOTIDE HYBRIDIZATION IN SYSTEMATIC CHARACTERIZATION OF MOLECULAR DEFECTS [J].

CHENG, TC ;

ORKIN, SH ;

ANTONARAKIS, SE ;

POTTER, MJ ;

SEXTON, JP ;

MARKHAM, AF ;

GIARDINA, PJV ;

LI, A ;

KAZAZIAN, HH .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1984, 81 (09) :2821-2825

[4]

Crooke S.T., 2008, Antisense Drug Technology: Principles, Strategies, and Applications, V2nd, P3

[5] RESTORATION OF CORRECT SPLICING IN THALASSEMIC PREMESSENGER RNA BY ANTISENSE OLIGONUCLEOTIDES [J].

DOMINSKI, Z ;

KOLE, R .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (18) :8673-8677

[6] Hemoglobinopathies in Southeast Asia: Molecular biology and clinical medicine [J].

Fucharoen, S ;

Winichagoon, P .

HEMOGLOBIN, 1997, 21 (04) :299-319

[7]

Gibbons R, 2001, THALASSAEMIA SYNDROM, P287

[8] An endogenous TNF-α antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models [J].

Graziewicz, Maria A. ;

Tarrant, Teresa K. ;

Buckley, Brian ;

Roberts, Jennifer ;

Fulton, LeShara ;

Hansen, Henrik ;

Orum, Henrik ;

Kole, Ryszard ;

Sazani, Peter .

MOLECULAR THERAPY, 2008, 16 (07) :1316-1322

[9]

JEARAWIRIYAPAIS.N, 2008, MOL THER IN PRESS

[10] Up-regulation of luciferase gene expression with antisense oligonucleotides: Implications and applications in functional assay developments [J].

Kang, SH ;

Cho, MJ ;

Kole, R .

BIOCHEMISTRY, 1998, 37 (18) :6235-6239

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