a possible new approach to treating beta-thalassaemia

Università Vita-Salute San Raffaele
In text 513Italy sadly heads the charts when it comes to one particular disease. The country has around 6,000 people suffering of beta-thalassaemia, also known as Mediterranean anaemia. Sardinia, in particular, is the Mediterranean region with the highest number of healthy carriers of beta-thalassemia, with around 1,000 people on the island being affected. Although considered a rare disease (thought to affect 1.5% of the world population), research into an effective cure is becoming increasingly necessary.
Dr. Antonella Nai, a young researcher at the Iron Metabolism Regulation Unit, headed by Prof. Clara Camaschella, has focused on this disease and on a possible new therapeutic approach. Antonella Nai was one of the winners of the Cariplo grant for “Biomedical research conducted by Young Researchers 2017". The funding (€ 250,000 for three years) will finance the project she coordinates, entitled Unraveling the role of TFR2 in the pathophysiology of beta-thalassemia for the development of a novel therapeutic approach”.
In this interview, our UniSR researcher tells us about what her study involves and how she plans on organising her research.



Our red blood cells contain a molecule called haemoglobin, which in adults is made up of four subunits called “chains”: two alpha chains and two beta chains. Each subunit in the haemoglobin molecule contains a haem group, which coordinates an iron atom and is responsible for transporting oxygen. Each haemoglobin molecule can therefore bind four oxygen molecules.
Beta-thalassaemia ( more correctly in the plural, beta-thalassaemias) is a disorder caused by mutations in the beta-globin gene; the two main forms are thalassaemia minor (caused by a mutation in the beta-globin gene, resulting in a slight reduction in beta chain synthesis) and thalassaemia major (when there are two mutations in the beta-globin gene, leading to a severe reduction in the beta chain or even its total absence). There is also a form called thalassaemia intermedia, midway between the forms described above in terms of its severity. Antonella explains: “When there is insufficient beta chain, alpha chain deposits build up in the red blood cells: this results in deformed red blood cells, anaemia, anomalous erythropoiesis (the red blood cell formation process), iron overload and, in the most severe cases, splenomegaly (enlarged spleen) and bone deformity.”
The treatments used today primarily involve subjecting patients to continuous blood transfusions associated with iron chelation treatments, which involve medication that bind and eliminate excess iron or bone marrow transplants when a donor is available. New treatments for thalassaemia are in the experimental phase. The group headed by Prof. Camaschella, a longstanding Full Professor of Internal Medicine at Vita-Salute San Raffaele University, and Dr. Nai in particular, have been working for a long time with Prof. Giuliana Ferrari, Full Professor of Molecular Biology at Vita-Salute San Raffaele University and Head of Department at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), whose laboratory primarily focuses on gene therapy for thalassaemia. “The clinical trial in patients with transfusion-dependent thalassaemia major is producing some encouraging results, particularly in younger patients, but it involves a complex and expensive approach, so there’s a great deal of interest in identifying alternative strategies, which are easier to use and can therefore be more effective across a broader spectrum”, explains Dr. Nai.


“Our project focuses on an iron protein called Tfr2 (transferrin receptor 2), primarily expressed in the liver, where it regulates iron availability, and on the surface of erythroblasts (progenitors of red blood cells, produced by the bone marrow, ed.). We have previously shown that Tfr2 has a surprising effect on normal erythropoiesis: the absence of Tfr2 significantly improves the maturation of red blood cell precursors, increasing their susceptibility to stimulation by erythropoietin (the hormone that regulates red blood cell production, ed.), so much so in fact that it even leads to an increase in red blood cells in normal rats”.
The objective of the project will therefore be to investigate and uncover the molecular role of Tfr2 in ineffective erythropoiesis in beta-thalassaemia. Preliminary findings suggest that, in a thalassaemia intermedia model (not dependent on transfusions), the absence of Tfr2 leads to a significant improvement in anaemia. "The final objective is to identify and test a molecule that selectively inhibits Tfr2 in animals with thalassaemia, so that it can be put forward as a new therapeutic agent for controlling ineffective erythropoiesis and improving anaemia in beta-thalassaemia.”
In the long term, observe the researchers, the beneficial effect of increased erythropoiesis will probably be limited due to iron consumption, which becomes inefficient combined with such enhanced erythropoiesis. “Because of this, we will pay particular attention to iron level alterations during the project, as this is a critical aspect of this disorder.”
Lastly, considering that studies to date have been conducted in a model of thalassaemia intermedia (less severe), “we would also like to validate the same approach in thalassaemia major”.
The project has been conducted with the Fondazione Cariplo, which is committed to supporting and promoting socially useful projects linked to art and culture, the environment, personal services and scientific research. More than 1,000 projects are carried out each year, for a total value of around € 150 million per season.
The Fondazione Cariplo has launched four inter-sector programmes that incorporate Cariplo's fundamental philanthropic values: innovation, focus on vulnerable social groups, opportunities for young people, and welfare for everyone. These four high-impact social programmes are: Cariplo Factory, AttivAree, Lacittàintorno, Cariplo Social Innovation.
Not simply a patron, but a driver of ideas.
Further information can be found at www.fondazionecariplo.it
Date: 12/07/2019
By: Eufemia Serena Putorti
Translation: TDR Translation Company
Editing: Victor Cojocaru