Abstract
Fetal globin is endogenous, normally integrated in hematopoietic stem cells in all humans, and available for reactivation. Inducing expression of fetal globin (γ-globin) gene expression to 60–70% of α globin synthesis produces β-thalassemia trait globin synthetic ratios, and has been shown to reduce anemia to mild levels which do not require regular blood transfusion. Several classes of therapeutics have induced γ-globin expression in β thalassemia patients, raised total hemoglobin levels, and even eliminated transfusion requirements in formerly transfusion-dependent patients, demonstrating proof-of-concept of the approach. However, prior generations of therapeutics were not readily feasible for widespread use. Currently, several recently discovered oral therapeutic candidates are more potent and/ or patientfriendly, requiring low oral doses, have distinct molecular mechanisms of action, and can be used in combination regimens. Tailoring therapeutic regimens to patient subsets stratified for solely β+ or a β0 globin mutation, and for quantitative trait loci (QTL) which modulate HbF and clinical severity, can guide more effective and informative clinical trials. These advancements provide methods for a rational approach to applying fetal globin gene induction in therapeutic regimens suitable for use in diverse thalassemia patient populations world-wide.
Highlights
Fetal globin is endogenous, normally integrated in hematopoietic β-thalassemia syndromes are common monogenic disorders worldstem cells in all humans, and available for reactivation
Inducing g-globin expression by even small increments is recognized as a powerful therapeutic avenue that should be most amenable to applying world-wide, as the g globin genes are universally present and normally integrated in hematopoietic stem cells.[1,2]
While only a chemotherapeutic drug, hydroxyurea, has been commercially available and has had variable effects in the thalassemias, several important principles for application have been defined in trials of prior generations of therapeutic candidates, and the recent discovery of new therapeutic candidates offers a renaissance for this approach
Summary
Normally integrated in hematopoietic β-thalassemia syndromes are common monogenic disorders worldstem cells in all humans, and available for reactivation. Tailoring theral peutic regimens to patient subsets stratified for solely β+ or a β0 gloia bin mutation, and for quantitative trait loci (QTL) which modulate HbF c and clinical severity, can guide more effective and informative clinical r trials These advancements provide methods for a rational approach to e applying fetal globin gene induction in therapeutic regimens suitable omm for use in diverse thalassemia patient populations world-wide. Inducing g-globin expression by even small increments is recognized as a powerful therapeutic avenue that should be most amenable to applying world-wide, as the g globin genes are universally present and normally integrated in hematopoietic stem cells.[1,2] While only a chemotherapeutic drug, hydroxyurea, has been commercially available and has had variable effects in the thalassemias, several important principles for application have been defined in trials of prior generations of therapeutic candidates, and the recent discovery of new therapeutic candidates offers a renaissance for this approach
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