The β-thalassaemias are a group of severe and rare anaemias with monogenic inheritance, a complex systemic phenotype and several treatment-related complications, caused by more than 300 mutations of the β-globin gene. Novel therapeutic protocols, most of which are based on still experimental treatments,
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The β-thalassaemias are a group of severe and rare anaemias with monogenic inheritance, a complex systemic phenotype and several treatment-related complications, caused by more than 300 mutations of the β-globin gene. Novel therapeutic protocols, most of which are based on still experimental treatments, show great promise but significant variability of success between patients. These strategies include chemical/molecular induction of the endogenous β-like γ-globin gene or the restoration of clinically relevant β-globin levels by gene therapy. A small number of modifiers with significant impact on disease penetrance, severity and efficacy of treatments are known, but most remain elusive. Improvements of existing treatment regimens and optimization and application of novel treatments will critically depend on the characterization of additional disease modifiers and the stratification of patients for customized treatment regimens. This requires extensive analyses based on “OMICS”, an English-language neologism which refer to different but connected fields in molecular biology and biochemistry, such as genomics, transcriptomics, exomics, proteomics, metabolomics. The major objective of OMICS is a collective characterization of pools of biological molecules (gene sequences, transcripts, proteins and protein domains) controlling biological structures, functions and dynamics, including several involved in pathological conditions. One of the most interesting observations of genomics in β-thalassaemias is the association between genomic sequences and high fetal haemoglobin (HbF) levels, in consideration of the fact that high HbF levels are usually associated with milder forms of β-thalassaemia. Related to this issue, is the possibility to predict response to different therapeutic protocols on the basis of genomic analyses. For instance, three major loci (Xmn1-HBG2 single nucleotide polymorphism, HBS1L-MYB intergenic region on chromosome 6q, and BCL11A) contribute to high HbF production. Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production in a collection of β-thalassemia and sickle cell disease (SCD) patients allowed the identification of genomic signatures associated with high HbF. Therefore, it can hypothesized that genomic studies might predict the response of patients to treatments based on hydroxyurea, which is at present the most used HbF inducer in pharmacological therapy of β-thalassaemia. Transcriptomic/proteomic studies allowed to identify the zinc finger transcription factor B-cell lymphoma/leukemia 11A (BCL11A) as the major repressor of HbF expression. The field of research on g-globin gene repressors (including BCL11A) is of top interest, since several approaches can lead to pharmacologically-mediated inhibition of the expression of g-globin gene repressors, leading to gglobin gene activation. Among these strategies, we underline direct targeting of the transcription factors by aptamers or decoy molecules, as well as inhibition of the mRNA coding g-globin gene repressors with shRNAs, antisense molecules, peptide nucleic acids (PNAs) and microRNAs. In this respect, the THALAMOSS FP7 Project (THALAssaemia MOdular Stratification System for personalized therapy of β-thalassemia, www.thalamoss.eu) aims develop a universal sets of markers and techniques for stratification of β-thalassaemia patients into treatment subgroups for (a) onset and frequency of blood transfusions, (b) choice of iron chelation, (c) induction of fetal hemoglobin, (d) prospective efficacy of gene-therapy. The impact of THALAMOSS is the provision of novel biomarkers for distinct treatment subgroups in β-thalassaemia (500–1000 samples from participating medical centres), identified by combined genomics, proteomics, transcriptomics and tissue culture assays, the development of new or improved products for the cell isolation, characterization and treatment of β-thalassaemia patients and the establishment of routine techniques for detection of these markers and stratification of patients into treatment groups. Translation of these activities into the product portfolio and R&D methodology of participating SMEs will be a major boost for them as well as for the field. THALAMOSS tools and technologies will (a) facilitate identification of novel diagnostic tests, drugs and treatments specific to patient subgroups and (b) guide conventional and novel therapeutic approaches for β-thalassaemia, including personalized medical treatments.