Thalassemia: a problem that involves blood and bones

Despite the apparent "simplicity" of the cause -- in many cases the modification of a single letter of DNA -- genetic diseases are quite complex. Beside the main clinical manifestation, there may be others, in different organs: although secondary, these complications have a major impact on the quality of life and therefore deserve to be studied. Exemplary in this regard is the case of thalassemias, inherited diseases characterized by chronic anemia due to a defect in hemoglobin, the protein in red blood cells that transports oxygen to tissues.

Overall, hereditary hemoglobin defects are the most common genetic diseases in the world, with health impacts that vary depending on the specific mutation and the amount of hemoglobin produced: in severe cases, anemia occurs as early as six months of age and can be fatal if left untreated. Quality of life and life expectancy have improved considerably over the past three decades, thanks to the use of transfusions and chelating drugs (i.e. drugs that "bind" iron, preventing its toxic accumulation). In some cases it is possible to cure the disease with hematopoietic stem cell transplantation, provided an appropriate bone marrow donor can be found, but in recent years the prospects have been further broadened by advanced therapies, such as gene therapy and genetic editing.

Along with restoring adequate hemoglobin levels, however, there are other important aspects to improving quality of life. For reasons that are still poorly understood, people with chronic anemia often experience bone problems typical of old age, such as osteopenia and osteoporosis: their bones are thinner and more fragile, with a greater tendency to fractures. Understanding why this happens is therefore important for finding strategies to better counteract this potentially disabling phenomenon. This is what researchers from the San Raffaele-Telethon Institute for Gene Therapy group at IRCCS Ospedale San Raffaele in Milan, led by Giuliana Ferrrari, Full Professor of Molecular Biology in UniSR, are doing: it is among the first in the world to devise a gene therapy protocol for the most severe form of thalassemia beta (see the first positive results described in Nature Medicine), are in parallel working to further investigate the molecular mechanisms associated with this complex disease, whose impact on the body is not limited to anemia.

Annamaria Aprile, researcher and project leader of the team, explains:

"Blood and bone are two tissues that are only seemingly distant. In fact, it is within the cavity of the bones that bone marrow, the source of the blood's cells, hematopoietic stem cells, is located. In this microenvironment, the stem cells interact with many other cells and factors. We therefore wondered whether the bone defects so often observed in thalassemia patients could cause alterations in this "dialogue" and thus in the hematopoietic stem cell".

After several experiments conducted in the mouse model of the disease and in patient cells confirmed this hypothesis, the researchers looked for a possible pharmacological target on which to act to restore the correct interactions. They thus focused on a hormone, fibroblast growth factor 23 (FGF23), already known to be a key molecule in the regulation of both bone metabolism and erythropoiesis, i.e. the formation of red blood cells.

"The more severe the anemia, the higher the FGF23 levels were," Aprile continued.

We therefore tried to inhibit its production in disease model mice by a peptide, a small portion of the protein. The results were encouraging: we observed both an increase in bone density and improved bone quality, with recovery of interactions between bone cells and hematopoietic stem cells".

The study, which bears the signature as the first name of Annamaria Aprile, has merited the pages of Science Translational Medicine and opens up exciting prospects for the future.

"This was an outstanding team effort. I would especially like to thank our internal collaborators from the Bone Metabolism Unit and clinical colleagues from Ospedale San Raffaele, Policlinico Ca' Granda in Milan, and the University of Palermo. Bone problems in thalassemia patients are not entirely avoidable with the current treatment regimen, even when it is followed scrupulously: this was confirmed by our analyses conducted on 40 patients treated at San Raffaele Hospital and Policlinico Ca' Granda in Milan. It is what in jargon is called an unmet medical need, something that needs to be worked on to improve the quality of life of these people. Access to transplantation - and even more so to advanced therapies - is by no means a given and will hardly be so for everyone in the future: that is why it is important in parallel to work on these aspects as well. Moreover, it is possible that FGF23 inhibition will prove to be an effective strategy against bone loss in the context of other diseases".