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Sequence-specific modification of a ß-thalassemia locus by small DNA fragments in human erythroid progenitor cells

^* IRCCS-CSS San Giovanni Rotondo, Italy and CSS-Mendel Institute, Rome, Italy;
^° Department of Comparative Biomedical Sciences, University of Teramo, Italy;
^# Department of Experimental Medicine and Pathology, University "La Sapienza", Rome, Italy;
^@ Department of Biomedical Sciences, "G. D’Annunzio" University Foundation, Chieti-Pescara, Italy;
^{^} Department of Transfusional Medicine, A.S.L.-Pescara, Italy

Correspondence: Alessia Colosimo, Department of Comparative Biomedical Sciences, University of Teramo, piazza Aldo Moro, 64100 Teramo, Italy. Phone: international +39.0861.266862. E-mail: acolosimo{at}unite.it

Gene therapy has been proposed as a definitive cure for ß-thalassemia. We applied a gene targeting approach, based on the introduction of small DNA fragments (SDF) into erythroid progenitor cells, to specifically modify the ß-globin gene sequence at codon 39. The strategy was first tested in normal individuals by delivering mutant SDF that were able to produce the ß39 (CT) mutation. Secondly, wild-type SDF were electroporated into target cells of ß39/ß39. ß-thalassemic patients to correct the endogenous mutation. In both cases, gene modification was assayed by allele-specific polymerase chain reaction of DNA and mRNA, by restriction fragment length polymorphism analysis and by direct sequencing.

Key words: gene targeting, gene therapy, ß-thalassemia, HBB gene.