Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Shape / drug effects
-
Erythrocytes / drug effects
-
Erythrocytes / pathology
-
Hemoglobins / genetics*
-
Hemoglobins / metabolism
-
Humans
-
Injections, Intravenous
-
Interleukin-12 / blood
-
Mice
-
Mutation / genetics*
-
Oligonucleotides / administration & dosage
-
Oligonucleotides / adverse effects
-
Oligonucleotides / pharmacology
-
RNA Precursors / genetics*
-
RNA Precursors / metabolism
-
RNA Splicing / drug effects
-
RNA Splicing / genetics
-
Thalassemia / blood
-
Thalassemia / genetics*
-
Thalassemia / therapy*
-
beta-Globins / genetics
Substances
-
Hemoglobins
-
Oligonucleotides
-
RNA Precursors
-
beta-Globins
-
Interleukin-12