Genome-based therapeutic interventions for β-type hemoglobinopathies

Abstract

For decades, various strategies have been proposed to solve the enigma of hemoglobinopathies, especially severe cases. However, most of them seem to be lagging in terms of effectiveness and safety. So far, the most prevalent and promising treatment options for patients with β-types hemoglobinopathies, among others, predominantly include drug treatment and gene therapy. Despite the significant improvements of such interventions to the patient’s quality of life, a variable response has been demonstrated among different groups of patients and populations. This is essentially due to the complexity of the disease and other genetic factors. In recent years, a more in-depth understanding of the molecular basis of the β-type hemoglobinopathies has led to significant upgrades to the current technologies, as well as the addition of new ones attempting to elucidate these barriers. Therefore, the purpose of this article is to shed light on pharmacogenomics, gene addition, and genome editing technologies, and consequently, their potential use as direct and indirect genome-based interventions, in different strategies, referring to drug and gene therapy. Furthermore, all the latest progress, updates, and scientific achievements for patients with β-type hemoglobinopathies will be described in detail.

Molecular genetics of β-thalassemia

“…However, these 2 modifiers do not wholly explain the clinical heterogeneity. [ 13 , 22 ] Recent advances in technology and reducing costs have prompted genome-wide association studies to derive genetic modifiers for such complex traits. [ 23 ]…”

“…Elucidation of the modifying effects of HbF and α-thalassemia has not been too difficult as these loci have an observable clinical effect and the genetic variants are common and thus would contribute significantly to disease burden. However, these 2 modifiers do not wholly explain the clinical heterogeneity [13,22] . Recent advances in technology and reducing costs have prompted genome-wide association studies to derive genetic modifiers for such complex traits [23] …”

“…However, these 2 modifiers do not wholly explain the clinical heterogeneity. [13,22] Recent advances in technology and reducing costs have prompted genome-wide association studies to derive genetic modifiers for such complex traits. [23] However, genotypic variability at known loci is still insufficient to explain the phenotypic variability between individuals with the same genotype.…”

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

“…This research activity involves interdisciplinary collaborations between researchers working in genetics, molecular biology, pharmacology, pharmaceutics, and organic chemistry and it is expected to discover useful information on the mechanisms of drug action (e.g., pharmacodynamics and pharmacokinetics), the identification of novel molecular targets, and the design of novel biomedicines [3][4][5]. Furthermore, the clinical application for the prediction of toxicity risk or beneficial effects could be helpful in numerous ways for several pathologies, including hemoglobinopathies [13,20,[23][24][25][26][27].…”

“…This aspect of the "Pharmacogenomics" endeavor has a clear impact on personalized treatments in precision medicine for patients carrying β-hemoglobinopathies, such as β-thalassemia and SCD [25][26][27][28][29][30]. In fact, with the help of pharmacogenomics studies, the administration of drugs and drug combinations could be optimized on the basis of the genetic characteristics of each individual [25][26][27].…”