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Minerva Biotecnologica 2009 December;21(4):187-96


language: English

Novel achievements in the search of alternative options for therapy of b-thalassemia

Gambari R.

BioPharmaNet and Laboratory for the Development of Gene and Pharmacogenomic Therapy of Thalassaemia, Biotechnology Centre of Ferrara University, Ferrara, Italy


Beta-thalassemias are a group of hereditary human diseases caused by more that 200 mutations of the human b-globin gene, leading to low or absent production of adult b-globin and excess of a-globin content in erythroid cells, causing ineffective erythropoiesis and low or absent production of adult hemoglobin (HbA). Recently, several achievements have been published, opening novel opportunities for the development of innovative therapeutic strategies for b-thalassemias. The possible interventions are based on research conducted at the levels of gene structure, transcriptional regulation, mRNA processing, protein synthesis. A first class of possible therapeutic strategies is based on targeting of the expression of g-globin genes and induction of fetal hemoglobin with the basic idea of subsituting the function of HbA (expressed in adults but defective or absent in b-thalassemic patients) with fetal hemoglobin (HbF, usually absent in adults). In addition to small molecules found to be effective for induction of HbF, naturally occurring protein factors, short oligonucleotides, and artificial transcription factors were also studied. Targeting a-globin gene expression was also followed to reduce the excess of a-globin production by b-thalassemic cells. Modification of the b-globin gene expression in b-thalassemic cells was achieved by gene therapy, correction of the mutated b-globin gene, RNA repair and employing the read-through approach for inducing HbA production in erythroid precursors from patients affected by b-thalassemia caused by stop codon mutations of the b-globin gene. In addition, cellular therapy was hypothesized for b-thalassemia, including reprogramming somatic cells of b-thalassemia patients. This issue is of great interest for the future cell-based therapy of b-thalassemia and takes advantage from the recent demonstration of the ability to generate induced pluripotent stem cells. The papers commented in this review support the concept that several approaches are expected to bring new hopes for the future concerning the therapy of thalassemia.

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