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Identification and validation of a new class of HDAC inhibitors able to induce HbF in thalassemic erythroid precursors.


In recent years, it has become widely recognized that many genetic disorders benefit by the inhibition of histone deacetylases (HDACs), being them chromatin-modifying enzymes that affect the acetylation status of histones and modulate gene expression. The interest in these class of inhibitors arose from studies linking an aberrant HDAC activity to a variety of human cancers. However, more recent works revealed that different non-cancer diseases, including hemoglobinopathies, can also be ameliorated by inhibition of these class of enzymes.
Hemoglobinopathies, such thalassemia and sickle diseases, are genetic defects characterized by abnormal structure or underproduction of the normal globin proteins of the hemoglobin molecule (Hb). Both the diseases are associated with morbidity due to severe anemia. During the last three decades, the possibility to chemically induce the expression of the gamma-globin protein was considered the most promising approach to the cure of ß-hemoglobinopathies. In fact gamma-globin is an effective surrogate of the ß-globin protein and is normally found in fetal hemoglobin (HbF). To such goal, several chemical classes of HbF inducers were identified, many of which did not reach the clinic due to low efficacy and specificity, or due to toxicity and carcinogenicity. For such reason, there is an urgent need in identifying molecular and pharmacological ways to increase the production of HbF with new agents which are well tolerated by patients. Several finding suggest that inhibition of the activity of histone deacetylases (HDAC)s is associated with an increased expression of the gamma-globin genes, hence, the hypothesis that HDAC might represent a pharmacological intervention aimed at increasing the levels of HbF.
The work we present here is part of THALAMOSS project (THALAssaemia MOdular Stratification System for personalized therapy of beta-thalassemia) funded by European Union’s Seventh Framework Programme for research, technological development and demonstration (grant agreement no. 306201) which aims at the identification of novel diagnostic tests, drugs and treatments specific for ß-thalassaemia patients.
Here, we describe new agents that induce HbF production with greater efficacy with respect to known HDAC inhibitors. These compounds are small molecules endowed with potent HDAC inhibitory activity, capable of inducing erythroid differentiation and human gamma-globin gene expression. Further, they are characterized by good pharmacokinetic properties in preclinical species, which are predictive of an improved therapeutic window in humans.
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