Sirolimus in Sickle Cell Disease


Department of Life Sciences and Biotechnology, University of Ferrara

The group headed by Roberto Gambari is recognized as one of the leading players in the study of fetal hemoglobin (HbF) induction in hemoglobin diseases.

More than 450 papers, published by Roberto Gambari and coworkers, are present in MedLine with H-INDEX = 47. Furthermore, they authored more than 12 patents.

Professor Gambari was the coordinator of the FP7 THALAMOSS Project (THALAssaemia Modular Stratification System for personalized therapy of beta thalassemia; grant no. 306201-FP7-Health-2012- INNOVATION-1) and leads University of Ferrara in an HORIZON-2020 project ULTRAPLACAD (ULTRAsensitive PLAsmonic devices for early CANCER DIAGNOSIS).

Recently the group headed by Professor Gambari has been involved in 2 different clinical trials in beta-thalassemia, opening new avenues for translational research and individualized medicine.


Sickle Cell Disease (SCD)

The term Sickle Cell Sisease (SCD) describes a group of inherited red blood cell disorders. People with SCD have abnormal hemoglobin, called hemoglobin S (HSS) or sickle hemoglobin, in their red blood cells, causing sickling of the same red cells, which produces episodes of pain and other symptoms.

In between episodes of sickling, people with SCD are normally well. Long-term complications can occur. Certain conditions can trigger sickling, such as cold, infection, lack of fluid in the body (dehydration) or low oxygen.

People who have SCD inherit two abnormal hemoglobin genes, one from each parent. In all forms of SCD, at least one of the two abnormal genes cause a person’s body to make hemoglobin S. When a person has two hemoglobin S genes, the disease is called sickle cell anemia. This is the most common and often most severe kind of SCD. Hemoglobin SC disease and hemoglobin Sß thalassemia are two other common forms of SCD.

SCD is a monogenic disorder, with a very peculiar geographic distribution. There is no doubt on the remarkable level of protection that the sickle cell trait provides against severe malaria, thus constituting a text book example of natural selection. As a consequence, the prevalence of the disease is high throughout large areas in sub-Saharan Africa, the Mediterranean basin, the Middle East, and India.

Migration to the American continent, mostly caused by slave trading in the past centuries, is the reason while the disease is relatively frequent in US.
Migration form the mentioned areas to Europe is the cause of the recent increase in SCD seen in EU.

Incidence and prevalence of the disease

The number of people suffering from SCD has substantially changed in the last few years by the immigration patterns.

Since the disease is mostly present in people of non-Caucasian origin, the presence of immigrants from areas with high incidence of the disease has a profound influence on the epidemiology of the disease.

The sickle cell trait is present in approximately 40 percent of the general population in some areas of Africa and is present in approximately 8-9 % of black Americans.
Sickle cell disease affects approximately one in every 350 African American newborns.

Recent estimates indicate that about 110.000 people are affected by the disease in EU and about 100.000 in US. In Italy more than 6.000 patients are present, however this figure is likely to increase in the future due to immigration. 


Rational basis of the project

It is known that an elevated level of fetal hemoglobin (HbF) in SCD patients may result in a relevant clinical improvement.
Sirolimus, already used as an immunosuppressant in transplanted patients, should act in SCD patients by inducing erythroid differentiation and expression of fetal hemoglobin, thus reducing the need of frequent blood transfusions and the appearance of pain crisis.

Indeed, the only drug currently approved in EU for the treatment of SCD, namely hydroxyurea (HU), acts by increasing HbF. HU application is limited in many cases by lack of efficacy and by side effects, thus new agents are actively searched.
Data obtained by Gambari’s group as well as by other scientists suggest that sirolimus (also known as rapamycin) may be able to increase HbF in patients with SCD.

Goal of the project

Sirolimus is a drug already widely used as 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 recently 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 SCD, sirolimus potently and dose dependently increased HbF and hemoglobin content, thus suggesting it may be an interesting candidate for a role in the treatment of patients with SCD.

RarePartners obtained Orphan Drug Designation for sirolimus use in SCD from both EMA and FDA and is presently working toward completion of preclinical studies aimed at a rapid transfer of the project to the clinical stage.