We have identified two new
histone deacetylase (
HDAC) inhibitors (9 and 24) capable of inducing the expression of
gamma-globin and/or
beta-globin promoter-driven reporter genes in a synthetic model of Hb switch. Both compounds also increased, with different mechanisms, the gamma/(gamma+beta) ratio expressed in vitro by normal human erythroblasts. Compound 9 increased the levels of
gamma-globin mRNA and the gamma/(gamma+beta) ratio (both by 2-fold).
Compound 24 increased by 3-fold the level of
gamma-globin and decreased by 2-fold that of
beta-globin mRNA, increasing the gamma/(gamma+beta) ratio by 6-fold, and raising (by 50%) the cell HbF content. Both compounds raised the acetylation state of
histone H4 in primary cells, an indication that their activity was mediated through HDAC inhibition. Compounds 9 and 24 were also tested as gamma/(gamma+beta)
mRNA inducers in erythroblasts obtained from patients with beta(0)
thalassemia. Progenitor cells from patients with beta(0)
thalassemia generated in vitro morphologically normal proerythroblasts that, unlike normal cells, failed to mature in the presence of EPO and expressed low
beta-globin levels but 10 times higher-than-normal levels of the alpha
hemoglobin-stabilizing
protein (AHSP)
mRNA. Both compounds ameliorated the impaired in vitro maturation in beta(0) thalassemic erythroblasts, decreasing AHSP expression to normal levels. In the case of two patients (of five analyzed), the improved erythroblast maturation was associated with detectable increases in the gamma/(gamma+beta)
mRNA ratio. The low toxicity exerted by compounds 9 and 24 in all of the assays investigated suggests that these new
HDAC inhibitors should be considered for personalized
therapy of selected patients with beta(0)
thalassemia.