RNA repair restores hemoglobin expression in IVS2-654 thalassemic mice.
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.
Svasti
Saovaros
S
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Suwanmanee
Thipparat
T
Fucharoen
Suthat
S
Moulton
Hong M
HM
Nelson
Michelle H
MH
Maeda
Nobuyo
N
Smithies
Oliver
O
Kole
Ryszard
R
D000818:Animals; D048430:Cell Shape / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D006454:Hemoglobins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000097:blood; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D013789:Thalassemia / Q000097:blood / Q000235:genetics* / Q000628:therapy*; D055544:beta-Globins / Q000235:genetics
D006454:Hemoglobins; D009841:Oligonucleotides; D012322:RNA Precursors; D055544:beta-Globins; D018664:Interleukin-12