Gene modifiers in β-thalassemia syndromes – a new therapy approach

β-talasemijski sindromi predstavljaju veoma heterogenu grupu naslednih oboljenja hemoglobina koje odlikuje poremećena sinteza β-globinskog lanca. Kliničke manifestacije β-talasmijskih sindroma variraju od asimptomatskog do teškog oblika ovih oboljenja koje odlikuje zavisnost pacijenata od čestih transfuzija. Velika fenotipska varijabilnost karakteristična za β-talasemije koja se najčešće ne može objasniti samo različitim alelskim varijantama unutar β-globinskog gena, usmerila je istraživanja ka genima modifikatorima ovih sindroma. Naime, smatra se da bilo koji faktor koji dovodi do smanjenja disbalansa između α - i β-globinskih lanaca predstavlja potencijalo važan modifikator β-talasemijskih sindroma. Tako, sinteza fetalnog hemoglobina i u adultnom dobu, delimično ublažava kliničku sliku jer se nedostatak funkcionalnog β-globinskog lanca kompenzuje viškom fetalnih, γ-globinskih lanaca. Brojne GWAS studije ukazale su na postojanje varijanti i van β-globinskog genskog lokusa koje utiču na ekspresiju γ-globinskih ili stabilnost α-globinskih lanaca, a samim tim i na fenotip β-talasemijskih sindroma (HBS1-MYB, BCL11A, AHSP, FoP, KLF1). Do skora, transplantacija kosne srži je bio jedini vid terapije β-talasemijskih sindroma, međutim usled visoke stope morbititeta i mortaliteta ove vrste terapije, alternativne strategije kao što su genska terapija i razvoj indukovanih pluripotentnih stem ćelija se ubrzano razvijaju. Cilj genske terapije β-talasemijskih sindroma je indukcija produkcije β- ili γ-globinskih lanaca kao i smanjenje α/β disbalansa u eritrocitima. Za transfer gena u genskoj terapiji koriste se različite vrste vektora, kako ne-virusni, tako i virusni. Napredak na polju razvoja različitih vrsta vektora, transdukcije humanih stem i progenitor ćelija, kao i različitih metoda editovanja samih gena, daje nadu da će u bliskoj budućnosti genska terapija biti terapija izbora za β-talasemijske sindrome.The β-thalassemia syndromes are heterogeneous hereditary hemoglobin disorders, characterized by defect in β-globin chain synthesis. Clinical manifestations of β-thalassemia vary from severe, transfusiondependent thalassemia major to mild, asymptomatic thalassemia trait. This phenotypic variability characteristic for β-thalassemia that usually cannot be explained only by variations affecting β-globin gene, swayed researchers toward identifying genetic modifiers for these disorders. Namely, any factor that reduces the imbalance between α- and β-globin polypeptide chains is considered to be an important modifier of this disorder. Specifically, production of fetal hemoglobin through adulthood could ameliorate the severity of β-thalassemia phenotype since γ-globin polypeptide chains compensate for the lack of the functional β-globin ones. GWAS studies have shown that regions outside of the β-globin gene cluster are also implicated in γ-globin gene expression regulation and α-globin chain stability, and hence, play an important role in β-thalassemia phenotype (HBS1-MYB, BCL11A, AHSP, FoP, KLF1). Until recently, a definitive cure for β-thalassemia could only be achieved through bone marrow transplantation. However, since its significant risk of morbidity and mortality, an alternative strategies, such as gene therapy and development of induced pluripotent stem cells have been explored. The goal of β-thalassemia gene therapy is the induction of β- or γ-globin polypeptide chains, as well as the reduction of α/β- chain disbalance in erythrocytes.Various types of vectors have been considered for gene transfer, including non-viral and viral. Recent improvements in vector biology and development, human stem cell transduction, as well as the availability of new gene-editing methodology, pave the way towards introduction of gene therapy as a go-to therapy for β-thalassemia syndromes