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Discovery of New Treatment Possibilities for Blood Disorders
A group of scientists have recently conducted two studies that will possibly make a contribution to discovery of cure for three hematological diseases: beta thalassemia, hemochromatosis and polycythemia vera.

In this extensive research project, 24 researchers from 6 scientific institutions across North America and Europe were involved and thanks to their great effort, iron metabolism and life cycle characteristics of red blood cells now seem to be much more clear.

"When you tease apart the mechanisms leading to these serious disorders, you find elegant ways to manipulate the system," says Dr. Stefano Rivella, associate professor of genetic medicine in pediatrics at Weill Cornell Medical College. He pointed out that although the genetic causes of hemochtomatosis and beta thalassemia are different, the consequences of that mutations are the same – iron overload. Therefore, the treatment which would eliminate the excess of iron from the body would be effective for both disorders.

The scientists then decided to take a closer look at the possibilities of controlling red blood cell production, as it seemed like a perfect way to treat thalassemia and polycytemia vera.

Erythropoesis and Iron Levels

The first study was published on March 17, 2013, and it focused on red blood cells production process called erythropoesis. That was the key for revealing pathological processes of two diseases – beta thalassemia and polycytemia vera.

Beta thalassemia is hematological disease which develops because of the mutation of the gene which carries information for synthesis of proteins that build hemoglobin. In thalassemia minor, only one of two beta hemoglobin chains is missing, so the symptoms are mild – slight mycrocyte anemia. In thalassemia major, on the other hand, two beta chains are missing leading to severe anemia. Distruction of blood cells leads to excess iron which accumulates in various organs and makes damage.

Hemoglobin chains in polycitaemia vera are normal, but there is a mutation of regulatory gene that should be limiting the production of red blood cells. As it doesn’t work properly, the main finding in this disease is increased number of circulating erythrocytes.

New Crucial Erythropoesis Regulator

Until now, it was well known that two crucial factors contribute to regulation of erythropoesis – hormone erythropoietin and iron level. In this research it was found that macrophages play important role in this process. Functions of macrophages are recognized long time ago; they digest extracellular pathogens, gather dead cells and tissues, and they are in one word “cleaners” of the body. Dr. Rivella discovered that macrophages are also crucial for the initiation of stress erythropoesis. He pointed out the importance of physical contact between macrophage and erythroblasts in order for erythropoesis to begin. "No one knew macrophages were a part of emergency red blood cell production. We now know they provide fuel to push red blood cell factories to work faster," says the study's lead author Dr. Pedro Ramos, a former postdoctoral researcher at Weill Cornell.

The Treatment Strategy

This discovery implies that by disabling macrophage activity, the excessive erythropoesis as pathological process in diseases mentioned above could be slowed down. That is why researchers conducted an experiment on mice with polycytemia vera by inactivating their macrophage cells. As a result, a normal production of red blood cells was established.

The benefits of this discovery for patients with beta thalassemia are also very predictable, bearing in mind the fact that their body is desperately trying to compensate genetic defect by accelerating erythropoesis, which is not effective.

And that is not the end, it seems that the process of inactivation of macrophages also slows down their other functions such as transporting the iron to erythroblasts. That way, the erythrocytes decrease not only in number but also in iron content and they become very much like normal erythrocyte.

"I estimate that up 30 to 40 percent of the beta-thalassemia population could benefit from this treatment strategy," Dr. Rivella says.
Another parallel made by Dr. Rivellaa emphasizes the similarities between the ways macrophages affect tumor growth and red blood cells proliferation in polycytemia. He says that polycytemia could be considered as a type of red blood cell tumor. His estimations are that 30-40 percent of people with thalassemia could benefit from this discovery.

Regulation of Iron Absorption Revealed

The second study, conducted by researchers from Weill Cornell and from Isis Pharmaceuticals of Carlsbad, Calif and published on March 25, 2013, focused on investigating iron metabolism. It is well known that decreased iron level causes anemia, and on the other hand, excessive amount of iron is toxic for almost all organs.

Hemochromatosis is a genetic disorder of iron metabolism with iron levels up to 7 times greater than in healthy persons. The common consequences of long-term increased iron level are liver cirrhosis, kidney failure, diabetes mellitus etc.

In this study, several molecules that regulate iron metabolism are detected and explained. Ferroportin is a transport protein located in the mucosa of the small intestine, and it is considered as an “iron gate”. The other protein has the regulatory function and it is called hepcidin or Hamp. If the food contains much iron, the level of Hamp increases leading to closing the iron gate, thus blocking the iron absorption. In patients with hemochromatosis and beta thalassemia, levels of Hamp are too low, leading to increased absorption of iron and consequently to high iron blood levels.

The Treatment Strategy

To solve this problem, scientists used an opposite disorder which occurs in childhood and is based on genetic mutation of Tmprss6 gene which causes increase of Hamp level, thus disabling iron absorption. Therefore, the research team leaders developed Tmprss6 blocker drug in order to increase Hamp expression in patients with beta thalassemia and hemochromatosis. The drug is designed to target mRNA transcribed from Tmprss6 gene, and change its configuration thus disabling translation process, process of protein synthesis. "When you destroy that RNA, you destroy the ability of the Tmprss6 to make any protein," Dr. Monia says. Dr. Rivella says that this technology could be implemented and used in clinical studies very soon.

As these disorders didn’t have a proper treatment so far, this discoveries are great hope for the patients in order to improve their quality of life.
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Blood disorders and Tmprss6

The proposed development of Tmprss6 inhibition as a therapy for diseases such as β-Thalassemia and HFE-related hemochromatosis described in the article above arose from research on the molecular basis of iron regulation. As mentioned in the article, inappropriately low expression of hepcidin (HAMP), as occurs in β-Thalassemia, causes iron overload. Tmprss6 is a serine protease which acts as a regulator of the HAMP activation pathway. Normally, Iron activates HAMP expression via the BMP receptor/SMAD pathway. Tmprss6 acts to block HAMP up-regulation by cleavage of the BMP co-receptor hemojuvelin, thus regulating iron absorption. In the study mentioned in the article, antisense oligonucleotides were used to target Tmprss6 in mouse models of β-Thalassemia and hemochromatosis, leading to amelioration of symptoms. This built on previous studies, for example a study from the Scripps Research Institute in the USA. In this study a mouse model of anaemia called ‘mask’ showed reduced absorption of dietary iron caused by high levels of hepcidin due to a splicing defect in Tmprss6. Overexpression of normal TMPRSS6 protein suppressed Hamp transcription via proximal promoter element(s). Thus TMPRSS6 was identified as an essential part of the pathway that detects iron deficiency via effects on Hamp transcription. Another study from the Vita-Salute San Raffaele University in Milan, Italy showed that homozygous loss of Tmprss6 in a mouse model called Hbb(th3/+) with a thalassemic phenotype resulted in improvement of the anemia and reduction in ineffective erythropoiesis, splenomegaly, and iron loading in these mice. Thus this paper provided proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in conditions such as β-Thalassemia. The promise of these studies has been further confirmed in the study referred to in the original article in this thread.


DU, X. et al., 2008. The serine protease TMPRSS6 is required to sense iron deficiency. Science (New York, N.Y.), 320(5879), pp. 1088-1092
GUO, S. et al., 2013. Reducing TMPRSS6 ameliorates hemochromatosis and ß-thalassemia in mice. The Journal of clinical investigation, 123(4), pp. 1531-1541
NAI, A. et al., 2012. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of ß-thalassemia. Blood, 119(21), pp. 5021-5029
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