A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

Abstract

Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', ‘drug rescue’, ‘drug re-tasking’ and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the “off-label” use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.

Combined approaches for increasing fetal hemoglobin (HbF) and de novo production of adult hemoglobin (HbA) in erythroid cells from β-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing

“…The search for fetal hemoglobin inducers is a fast-moving field aiming to bring this approach from the laboratory to clinical settings. Review articles on HbF inducers are available discussing updates and the most recent findings ( Gambari and Fibach, 2007 ; Sripichai and Fucharoen, 2016b ; Lohani et al, 2018 ; Langer and Esrick, 2021 ; Bou-Fakhredin et al, 2022 ; Hashemi and Ebrahimzadeh, 2022 ; Prosdocimi et al, 2022 ). For preliminary screening of fetal hemoglobin inducers several in vitro cellular systems have been employed, such as In this case, several cellular model systems for the screening of HbF inducers are available, such as the K562 erythroleukemia cell line ( Gambari and Fibach, 2007 ) or the HUDEP-1 cell line derived from umbilical cord blood cells ( Papasavva et al, 2021 ).…”

The anti-SARS-CoV-2 BNT162b2 vaccine suppresses mithramycin-induced erythroid differentiation and expression of embryo-fetal globin genes in human erythroleukemia K562 cells

“…Accordingly, K562 cells have been used not only as a model system to study the regulation of the expression of embryo-fetal globin genes [38], but also as a model system for the screening of inducers of HbF, of potential interest in the therapy of β-thalassemia and sickle-cell disease (SCD) [37]. In fact, it is well established that HbF production is beneficial for both β-thalassemia and SCD [39].…”