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*Thalassemia
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Proc. Natl. Acad. Sci. USA
Vol. 93, pp. 12840-12844, November 1996
Biochemistry

Repair of thalassemic human beta -globin mRNA in mammalian cells by antisense oligonucleotides

(RNA splicing / gene therapy)

Halina Sierakowska*, Maria J. Sambade*, Sudhir AgrawalDagger , and Ryszard Kole*

* Lineberger Comprehensive Cancer Center and Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599; and Dagger  Hybridon, Inc., Worcester, MA 01605

Communicated by Y. W. Kan, University of California, San Francisco, CA, September 3, 1996 (received for review April 4, 1996)

In one form of beta -thalassemia, a genetic blood disorder, a mutation in intron 2 of the beta -globin gene (IVS2-654) causes aberrant splicing of beta -globin pre-mRNA and, consequently, beta -globin deficiency. Treatment of mammalian cells stably expressing the IVS2-654 human beta -globin gene with antisense oligonucleotides targeted at the aberrant splice sites restored correct splicing in a dose-dependent fashion, generating correct human beta -globin mRNA and polypeptide. Both products persisted for up to 72 hr posttreatment. The oligonucleotides modified splicing by a true antisense mechanism without overt unspecific effects on cell growth and splicing of other pre-mRNAs. This novel approach in which antisense oligonucleotides are used to restore rather than to down-regulate the activity of the target gene is applicable to other splicing mutants and is of potential clinical interest.


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