Sirolimus in beta-thalassemia


ThalLab - University of Ferrara

The Laboratory for the development of genetic and pharmacogenomic therapy of thalassemia has been activated following an Agreement of collaboration between the Center of Biotechnology of University of Ferrara (CBF) and the Associazione Veneta per la Lotta alla Talassemia (A.V.L.T.) of Rovigo.

Associazione Veneta per la Lotta alla Talassemia

Associazione Veneta per la Lotta alla Talassemia (A.V.L.T.)  is a non profit organization established since 1976 in Rovigo, Italy. Its mission is to promote different initiatives aimed at providing the best social and healthcare treatment for thalassemia sufferers.




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.

Incidence of the disease

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.


Rational basis of the project

Bone Marrow Transplantation (BMT) remains the only definitive cure currently available for patients with β-thalassemia, however its widespread application will be unlikely in the next future.
Gene therapy appears to be a promising way to treat the disease, but it is still at an early stage and will not be available in many countries for the near future.

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.

Goal of the project

Sirolimus (also known as rapamycin) is a drug already widely used, indeed it is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients receiving renal transplants.

Sirolimus causes immunosuppressive effects through inhibition of T and B-cell activity, however it has other important biological activities, not related to the action on T and B cells. 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.

RarePartners obtained Orphan Drug Designation for sirolimus use in beta-thalassemia from both EMA and FDA and has now started the process of clinical validation.
The first proof of concept clinical trial is currently ongoing at the University Hospital of Ferrara. Patient enrollment has started in September 2019 and first results are expected in the first half of 2021.

Furthermore, in parallel with this first study, RarePartners is collaborating with Prof. Gambari for a second clinical trial financed by a grant from AIFA, also in this case aiming at studying the efficacy of sirolimus in beta-thalassemia patients, that will be runned in three different locations, namely Ferrara, Firenze and Pisa.