Thalassemias are a heterogeneous group of hemoglobinopathies whereby a reduction in synthesis/stability of α or β globin chain causes α- or β-thalassemia, respectively. The clinical problem is excess β peptides (in α-thalassemia) or excess α peptides (in β-thalassemia); this imbalanced α:β ratio leads to early cell destruction and iron overload. The chain produced at a normal rate becomes relatively overabundant, eventually precipitating in the cell, damaging the membrane and causing premature hemolysis.
The heterozygote advantage is that thalassemias weaken red blood cells and confer some resistance to malaria. Upon infection, the cell just dies and prevents spread. Individuals that are α-α-/α-α- die in utero, although this does not include heterozygous mutations in different globin genes. Expression of the globin gene locus is managed by a locus control region (LCR).
|Drug Therapy||Possible drug therapy to influence LCR to prolong γ-globin (fetal) expression.|
|Gene Therapy||Using a lentivirus vector to add back normal β-globin gene or normal γ-globin (fetal) genes. Attempts without a new LCR failed; additions require the LCR for consistent, strong globin expressionAdditions require LCR in the construct for consistent, strong globin expression. Early attempts failed without the LCR.|
β-globin deficiency. Mostly due to single base-pair substitutions in the β-globin genes. Much more heterogenous than α thalassemias, even in high frequency populations. Complex β thalassemias involve β globin plus one or more of the genes from the β globin cluster LCR. β globin cluster is totally dependent on its LCR for expression.
Due to α-globin deficiency. Excess γ-globin chain form g4 tetramer (Hb Bart’s). Excess β-globin chains form b4 tetramer ( Hb H). These are ineffective oxygen carriers.