Associazione Veneta per la Lotta alla Talassemia
ThalLab - Università di Ferrara



The word thalassemias indicates a group of inherited disorders that affects the amount and type of hemoglobin a person produces.
Beta-thalassemia (β-thalassemia) is due to mutations in one or both of the beta globin genes, leading to abnormal red blood cells. The different types of β-thalassemia include:

  • β-thalassemia trait, including subjects that usually experience no health problems other than microcytosis and a possible mild anemia that will not respond to iron supplement. This gene mutation can be passed on to the individual’s children.
  • Thalassemia intermedia, including subjects with anemia requiring medical treatment.
  • Thalassemia major (known also as Cooley's Anemia), including subjects with anemia requiring lifelong regular blood transfusions and considerable ongoing medical care. Over time, these frequent transfusions lead to excessive amounts of iron in the body.

The dividing line between thalassemia intermedia and thalassemia major are the degree of anemia and the number and frequency of blood transfusions required to treat it. People with thalassemia intermedia may need occasional transfusions but do not require them on a regular basis.

β-thalassemia is most common in persons of Mediterranean, African and Southeast Asian descent, where thalassemia trait affects 5 to 30 percent of population, most likely related to the selective pressure from Plasmodium Falciparum Malaria.

It has been estimated that about 1.5% of the global population (80 to 90 million people) are carriers of β-thalassemia trait, with about 60,000 symptomatic individuals born annually, the great majority in the developing world. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 people throughout the world and 1 in 10,000 in the European Union.



Use of sirolimus in β-thalassemia

In some patients affected by β-thalassemia an anomalous expression of gamma globin genes has been observed, with a consequent raise in the level of HbF (Fetal Hemoglobin) from 2.5% to 20%. This high level of HbF causes a clinical phenotype known as HPFH (Hereditary Persistence of Fetal Hemoglobin).
Patients with HPFH exhibit a positive clinical status, since the activation of gamma-globin genes is associated with an increase of HbF, and this partly overcomes the problems caused by the lack of HbA (Adult Hemoglobin) in thalassemia syndromes.

With the aim of mimic the HPFH phenotype, several research groups have evaluated compounds able to induce erythroid differentiation and expression of embryo-fetal hemoglobins. Furthermore, clinical evidence obtained with a compound originally developed for other indications (Hydroxyurea, also known as Hydroxycarbamide, an antineoplastic agent) indicates that it is possible to increase HbF in thalassemic patients and this may result in a clinical improvement, such as reduced transfusion frequency.

Sirolimus (also known as rapamycin) is a drug already widely used as immunosuppressive agent for the prophylaxis of organ rejection in patients receiving renal transplants. Sirolimus causes immunosuppressive effects through inhibition of T and B-cell activity. Sirolimus has been studied in several different pathological conditions and has been authorized in US and EU for the treatment of lymphangioleiomyomatosis (LAM).
Sirolimus induces erythroid differentiation of the human leukemic K562 cell line and increases HbF production in primary human erythroid precursor cells. Furthermore, when tested on human erythroid precursor cells from peripheral blood of patients with β-thalassemia, sirolimus potently and dose dependently increased HbF and hemoglobin content, thus suggesting a potential role in patients affected by β-thalassemia.
Rare Partners, after having obtained the Orphan Drug Designation for sirolimus use in beta-thalassemia from both EMA and FDA, has supported the execution of two clinical trials in transfusion dependent patients affected by  β-thalassemia.

The first clinical trial, that received an important financial support from Wellcome Trust Foundation, has been carried out at the University Hospital of Ferrara and completed in 2022.

The second multicenter clinical trial, financed by AIFA and involving the Hospitals of Ferrara, Florence and Pisa, has been completed in 2024 and has been coordinated by Prof. Gambari of Ferrara University, who directed for many years the research work that identified the potential use of sirolimus in hemoglobinopathies.
The results from Prof. Gambari’s work and from clinical trials have been disclosed in several scientific papers, some of which having Dr. Marco Prosdocimi of Rare Partners as co-author.

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