5613398 A DRUG REPOSITIONING PROJECT FOR Β-THALASSEMIA: SIROLIMUS AND CINCHONA ALKALOIDS

Abstract

Background: Effective interactions between universities, patient organizations, and industries are a key factor in organizing competitive projects against rare diseases, including b-thalassemia. One of the missions of the “Center Chiara Gemmo and Elio Zago for the Research on Thalassemia” (Ferrara University, Italy) is to propose clinical trials based on orphan drug designation of repurposed compounds for β-thalassemias. In this communication, we present updates on sirolimus and cinchona alkaloids. Drug repositioning has gained attention in the field of rare diseases, and represents a relevant novel drug development strategy. A key advantage of drug repurposing over traditional drug development is that the repositioned drug has already passed toxicity, pharmacokinetic and pharmacodynamic tests, significantly reducing the probability of project failure, the time needed to reach the market and overall costs. Results: As far as sirolimus, a fetal hemoglobin (HbF) inducer, the biochemical, molecular and clinical results of the NCT03877809 clinical trial suggest that expression of γ-globin mRNA increases in 8 β-thalassemia patients (β+/β+ and β+/β0) treated with low-dose sirolimus (1 mg/day sirolimus). A second important conclusion of the trial was that sirolimus influences erythropoiesis and reduces biochemical markers associated with ineffective erythropoiesis. In most of the patients, a decrease of the transfusion demand index was observed [1]. Moreover, a recent study identified Cinchona alkaloids as natural HbF-inducing agents [2]. Two highly active compounds, cinchonidine and quinidine, were able to induce γ-globin mRNA and HbF in ErPCs isolated from β-thalassemia patients, strongly indicating that these compounds deserve consideration in the development of pre-clinical approaches for therapeutic protocols of β-thalassemia. These compounds should be considered as repurposed drugs, as quinidine has been employed in a variety of cardiac complications, such as arrhythmias, atrial fibrillation, idiopathic ventricular fibrillation, Brugada syndrome, and Short QT syndrome. Conclusion: HbF induction can be combined with novel therapeutic approaches, such as gene editing. We have recently reported the efficient correction, by CRISPR-Cas9 gene editing, of the β039-thalassemia mutation in ErPCs from homozygous β039-thalassemia patients [3]. Accumulation of corrected β-globin mRNA and relevant “de novo” production of β-globin and adult hemoglobin (HbA) were found. We are at present verifying whether co-expression of HbF and HbA can be achieved using HbF inducers and CRISPR-Cas9 gene editing in combinantion.