MINERVA BIOTEC 2008;20:51-5 Gene silencing in thalassemia N. BIANCHI, M. BORGATTI, R. GAMBARI The β-thalassemias are characterized by a very hetero- geneous group of inherited mutations causing abnor- mal expression of globin genes, leading to total absence or quantitative reduction of synthesis of β-globin chains. The reduction of β-globin chains is associated with a corresponding excess of the complementary α-globin chains in erythroid cells, causing premature hemoly- sis of red blood cells and destruction of erythroid pre- cursors in the bone marrow and extramedullary sites (ineffective erythropoiesis). Several molecules appear to be not necessary or even harmful to the erythroid cell, i.e. abnormal β-globin mRNA molecules (for instance in the case of aberration of splicing) and α-globin mRNA molecules, present in large excess. In agreement, inhi- bition of the expression of abnormal β- or α-globin mRNAs could be beneficial. Gene silencing could be of interest also in experimental therapy employing acti- vation of the expression of human γ-globin genes by interfering with transcriptional repressors. The con- clusion of the experiments described in the present review is that experimental therapy of β-thalassemia is commonly dedicated to induce the forced expression (by gene therapy and gene corrections of the mutations) of the adult not functional β-globin gene. On the other hand induction of fetal γ-globin genes can be achieved by inhibiting putative transcription repressors. Finally, GenTech-for-Thal, Department of Biochemistry and Molecular Biology University of Ferrara, Ferrara, Italy Laboratory for the Development of Pharmacological and Pharmacogenomic Therapy of Thalassaemia Biotechnology Center University of Ferrara, Ferrara, Italy in addition to this primary issue, the inhibition of the excess of α-globin mRNA might turn to be an approach able to ameliorating the clinical parameters of β-tha- lassemia. Key words: Gene silencing - Oligonucleotides - Globins - Fetal hemoglobin - Beta-thalassemia. T he β-thalassemias are characterized by a very het- erogeneous group of inherited mutations causing abnormal expression of globin genes, leading to total absence or quantitative reduction of synthesis of β-glo- bin chains. 1-3 This disease is frequent in the Mediter- ranean area, in Middle-East, in Africa and Asia. The reduction of β-globin chains is associated with a corre- sponding excess of the complementary α-globin chain in erythroid cells, that causes premature hemolysis of red blood cells and destruction of erythroid precursors in the bone marrow and extramedullary sites (ineffective ery- thropoiesis) (Figure 1). 4-8 More than 200 different muta- tions have been identified in β-thalassemia patients, 1, 7, 9 including deletions of the β or δβ gene region, stop codons leading to premature termination of a non func- tional β-globin chain, mutations suppressing correct maturation of the β-globin RNA precursor. 9 Acknowledgements and Fundings.—R.G. is granted by Fondazione Cariparo (Cassa di Risparmio di Padova e Rovigo), AIRC, Cofin-2005, by STAMINA Project (University of Ferrara), by UE ITHANET Project (eInfrastructure for the Thalassaemia Research Network) and by Telethon (contract GGP07257). This research is also supported by Regione Emilia- Romagna (Spinner Project) and by Associazione Veneta per la Lotta alla Talassemia (AVLT), Rovigo. Received on May 25, 2008. Accepted for publication on June 3, 2008. Address reprint requests to: R. Gambari, Department of Biochemistry and Molecular Biology, University of Ferrara, Via Fossato di Mortara 74, 44100 Ferrara, Italy. E-mail: gam@unife.it Vol. 20 - No 1. MINERVA BIOTECNOLOGICA 51