The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Abstract

In this review article, we present the fascinating story of rapamycin (sirolimus), a drug able to induce γ-globin gene expression and increased production of fetal hemoglobin (HbF) in erythroid cells, including primary erythroid precursor cells (ErPCs) isolated from β-thalassemia patients. For this reason, rapamycin is considered of great interest for the treatment of β-thalassemia. In fact, high levels of HbF are known to be highly beneficial for β-thalassemia patients. The story of rapamycin discovery began in 1964, with METEI, the Medical Expedition to Easter Island (Rapa Nui). During this expedition, samples of the soil from different parts of the island were collected and, from this material, an antibiotic-producing microorganism (Streptomyces hygroscopicus) was identified. Rapamycin was extracted from the mycelium with organic solvents, isolated, and demonstrated to be very active as an anti-bacterial and anti-fungal agent. Later, rapamycin was demonstrated to inhibit the in vitro cell growth of tumor cell lines. More importantly, rapamycin was found to be an immunosuppressive agent applicable to prevent kidney rejection after transplantation. More recently, rapamycin was found to be a potent inducer of HbF both in vitro using ErPCs isolated from β-thalassemia patients, in vivo using experimental mice, and in patients treated with this compound. These studies were the basis for proposing clinical trials on β-thalassemia patients.

Increased Expression of α-Hemoglobin Stabilizing Protein (AHSP) mRNA in Erythroid Precursor Cells Isolated from β-Thalassemia Patients Treated with Sirolimus (Rapamycin)

“…[43]. These data strongly support the concept that sirolimus, in addition to the reported effects on HbF and γ-globin gene expression [35,36,39,43,47], is able to activate programs controlling the excess to α-globin production, ultimately reducing ineffective erythropoiesis. In order to verify whether the sirolimus-mediated effect on AHSP mRNA also occurs in vivo in sirolimus-treated β-thalassemia patients, we took advantage of the clinical trial NCT03877809 (Sirthalaclin).…”

“…Sirolimus (rapamycin) is one of the most promising drugs for inducing HbF [35][36][37][38]] and, at the same time, ULK1-mediated autophagy [19,20]. The several applications of sirolimus in biomedicine, from its discovery to its possible use in clinical trials, have been recently reviewed [39]. Sirolimus was first demonstrated to be a potent anti-bacterial and anti-fungal agent.…”

“…Later, it was found to inhibit the in vitro cell growth of tumor cell lines. More importantly, for biomedical applications in the field of organ transplantation, sirolimus exhibits immunosuppressive activity [39]. More recently, sirolimus was found to be a potent inducer of fetal hemoglobin (HbF) in erythroid precursor cells isolated from normal subjects and β-thalassemia patients [35,36], in experimental in vivo mouse model systems [37,38] and in patients under sirolimus treatment [40,41].…”

“…More recently, sirolimus was found to be a potent inducer of fetal hemoglobin (HbF) in erythroid precursor cells isolated from normal subjects and β-thalassemia patients [35,36], in experimental in vivo mouse model systems [37,38] and in patients under sirolimus treatment [40,41]. Considering these activities, sirolimus was proposed as a repurposed drug of possible interest for clinical trials on β-thalassemia patients [39,42,43].…”

Therapeutic Relevance of Inducing Autophagy in β-Thalassemia

“…Their data support the concept that autophagy, Ulk1 increased expression, and α-globin chain reduction are activated in β-thalassemia patients who take a daily dosage of 2 mg rapamycin (sirolimus). The experimental evidence and technology-transfer activities sustaining sirolimus-based clinical trials have been recently reviewed [ 101 ]; information on the NCT03877809 clinical trial can be found in Gamberini et al [ 102 ], while the first report on the results of the trial has been published by Zuccato et al [ 103 ]. The main results of the trial, reported by Zuccato et al [ 103 ], were that the content of γ-globin RNA and HbF are increased in ErPCs isolated from sirolimus-treated β-thalassemia patients.…”