Pharmacogenomics of Drugs Used in ß-Thalassemia and Sickle-Cell Disease: From Basic Research to Clinical Applications.

In this short review we have presented and discussed studies on pharmacogenomics (also termed pharmacogenetics) of the drugs employed in the treatment of ß-thalassemia or Sickle-cell disease (SCD). This field of investigation is relevant, since it is expected to help clinicians select the appropriate drug and the correct dosage for each patient. We first discussed the search for DNA polymorphisms associated with a high expression of γ-globin genes and identified this using GWAS studies and CRISPR-based gene editing approaches. We then presented validated DNA polymorphisms associated with a high HbF production (including, but not limited to the HBG2 XmnI polymorphism and those related to the BCL11A, MYB, KLF-1, and LYAR genes). The expression of microRNAs involved in the regulation of γ-globin genes was also presented in the context of pharmacomiRNomics. Then, the pharmacogenomics of validated fetal hemoglobin inducers (hydroxyurea, butyrate and butyrate analogues, thalidomide, and sirolimus), of iron chelators, and of analgesics in the pain management of SCD patients were considered. Finally, we discuss current clinical trials, as well as international research networks focusing on clinical issues related to pharmacogenomics in hematological diseases.

Sickling-preventive effects of rutin is associated with modulation of deoxygenated haemoglobin, 2,3-bisphosphoglycerate mutase, redox status and alteration of functional chemistry in sickle erythrocytes.

Sickle cell anaemia is a hereditary disease branded by an upsurge in generation of ROS, irregular iron release and little or no antioxidant activity which can lead to cellular injuries due to oxidative stress resulting in severe symptoms including anaemia and pain. The disease is caused by a mutated version of the gene that helps make haemoglobin, the protein that carries oxygen in red blood cells. We used in silico and in vitro experiments to examine the antisickling effects of rutin for the first time by means of before and after induction approaches in sickle erythrocytes. Rutin was docked against deoxy-haemoglobin and 2,3-bisphosphoglycerate mutase, revealing binding energies (-27.329 and -25.614 kcal/mol) and Ki of 0.989µM and 0.990 µM at their catalytic sites through strong hydrophobic and hydrogen bond interactions. Sickling was thereafter, induced at 3 h with 2% metabisulphite. Rutin prevented sickling maximally at 12.3µM and reversed same at 16.4µM, by 78.5% and 69.9%, one-to-one. Treatment with rutin significantly (P < 0.05) reinvented the integrity of erythrocytes membrane as evident from the practical % haemolysis compared to induced erythrocytes. Rutin also significantly (P < 0.05) prevented and reversed lipid peroxidation relative to untreated. Likewise, GSH, CAT levels were observed to significantly (P < 0.05) increase with concomitant significant (P < 0.05) decrease in SOD activity based on administration of rutin after sickling induction approach. Furthermore, FTIR results showed that treatment with rutin favourably altered the functional chemistry, umpiring from shifts and functional groups observed. It can thus be deduced that, antisickling effects of rutin may be associated with modulation of deoxy-haemoglobin, 2,3-bisphosphoglycerate mutase, alteration of redox homeostasis and functional chemistry of sickle erythrocytes.