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JAK2 inhibitor

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love and prayers:
Avoiding spleen removal for Cooley's anemia sufferers
Published: Wednesday, May 28, 2008 - 20:28 in Health & Medicine
Researchers from Weill Cornell Medical College may have discovered the precise role of a gene in one of the world's most common blood disorders, beta-thalassemia, commonly known as Cooley's anemia. Along with sickle-cell anemia, Cooley's anemia is the most commonly inherited disease in the world, affecting many people of Mediterranean descent, and 20 out of every 100,000 African-Americans. The World Health Organization estimates that between 50,000-100,000 children are born with the disease each year. The research is published in the latest online issue of the journal Blood, the official publication of the American Society of Hematology (ASH).

In Cooley's anemia, hemoglobin -- the oxygen-carrying molecule on red blood cells -- is mutated and non-functioning, resulting in a low red-blood-cell count. Common symptoms of the disease include fatigue, shortness of breath and an enlarged spleen, called splenomegaly, caused by a buildup of malformed red blood cells within the body. The spleen works to filter out these unhealthy cells in order to protect the body from harm, such as in a stroke, but eventually the spleen becomes over-stuffed and is commonly surgically removed (splenectomy) in order to prevent a potentially fatal burst. Unfortunately, after the spleen is removed, patients are at a much greater risk for stroke and infections.

Dr. Stefano Rivella, the study's senior author and assistant professor of genetic medicine in pediatrics at Weill Cornell Medical College, in New York City, believes that he and his collaborators may have found a way around splenectomy. After giving mice with Cooley's a compound called JAK2 inhibitor, the researchers found that the mice's spleens shrunk to normal sizes, and they began to produce normal red blood cells. The chemical (a similar compound is already in a Phase I clinical trial for myelodysplastic syndromes -- another blood disorder) blocks the activity of the JAK2 gene that is highly expressed in Cooley's anemia, and is believed to play a crucial role in the malformation of red blood cells.


does anyone know about the clinical trial?
it may be beneficial for us.

ironjustice:
Too much Jak2 causes polycythemia / erythrocytosis.

http://www.nhlbi.nih.gov/health/dci/Diseases/poly/poly_causes.html


What Causes Polycythemia Vera?
Polycythemia vera (PV) also is known as primary polycythemia. A
mutation, or change, in the body's JAK2 gene is the main cause of PV.
The JAK2 gene makes an important protein that helps the body produce
blood cells.


What causes the change in the JAK2 gene isn't known. PV generally
isn't passed from parent to child. However, in some families, the JAK2
gene may have a tendency to mutate. Other, unknown genetic factors
also may play a role in causing PV.

Andy Battaglia:
I do not believe that this has been scheduled for trial in humans yet. The studies were done using mice. Dr Rivella gave a talk on the subject of Jak2 inhibitors the the NYC conference in 2009. Sharmin and I were at the lecture. This is the abstract from that lecture. This is from the New York Academy of Science site.


--- Quote ---Iron Regulation And Ineffective Erythropoiesis, Jak 2

Luca Melchiori, PhD1, Sara Gardenghi, PhD1, Ella Guy1, MD.2, Domenica Cappellini, MD3, MD1, Robert W. Grady, PhD.1, Stefano Rivella, PhD1 , 1Department of Pediatric Hematology-Oncology, Weill Medical College of Cornell University, New York, NY; 2E. Wolfson Medical Centre, Institute of Hematology, Holon, Israel, 3Centro Anemie Congenite, Fondazione Policlinico, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Milan, Milan, Italy

In thalassemia, ineffective erythropoiesis is characterized by apoptosis of the maturing nucleated erythroid cells. Our studies also suggest that limited erythroid cell differentiation plays a role in the development of ineffective erythropoiesis. Some of the major consequences of ineffective erythropoiesis are extra−medullary hematopoiesis (EMH), splenomegaly and systemic iron overload mediated by transfusion therapy and down−regulation of hepcidin. Recall that under conditions of chronic anemia, low levels of hepcidin lead to iron overload. We hypothesized that the protein kinase Jak2, which controls erythroid cell proliferation, plays a major role in exacerbating ineffective erythropoiesis. Therefore, use of Jak2 inhibitors may limit the overproduction of immature erythroid cells in thalassemia, with the potential of reversing extramedullary hematopoiesis and preventing splenectomy. For this reason, we administered a Jak2 inhibitor to mice affected by beta−thalassemia intermedia for 10 days, showing that this treatment was associated with a marked decrease in ineffective erythropoiesis, splenomegaly, no or with little or no reduction of red cell production and no side effects.

There is a clear correlation between the mass of erythroid precursors and suppression of hepcidin. Therefore, administration of a Jak2 inhibitor might also be associated with increased hepcidin synthesis and decreased iron absorption. In order to test this hypothesis we repeated the above-mentioned study in order to evaluate the level of hepcidin expression as well as that of other iron related genes. This analysis clearly indicated that the size of the spleen inversely correlated with hepcidin synthesis. In addition, blood transfusion is a pre-requisite for the management of both thalassemia−major patients and those with thalassemia−intermedia who develop splenomegaly. Therefore, administration of a Jak2 inhibitor, together with blood transfusions, might be a sensible way to further suppress ineffective erythropoiesis and limit splenomegaly/EMH. We conducted an analysis of erythropoiesis and iron metabolism in animals affected by beta−thalassemia major, which require blood transfusion for survival and compared them to transfused animals treated with placebo. Compared to latter controls, the animals treated with the Jak2 inhibitor showed a dramatic decrease in splenomegaly, amelioration of the spleen architecture and complete elimination of EMH in the liver. In addition, due to the reduction of the size of the spleen, the animals treated with the Jak2 inhibitor showed higher levels of hemoglobin at the end of the treatment, again, the spleen size inversely correlating with hepcidin synthesis. These experiments suggest that this class of compounds, if safe, might be an important tool to prevent splenectomy, reverse EMH, limit iron absorption and improve the effectiveness of transfusion therapy in patients with thalassemia.
--- End quote ---

At this point, it is one more potential approach to treating thalassemia. I am posting the abstracts from the entire session at
http://www.thalassemiapatientsandfriends.com/index.php?topic=3823.msg38437#msg38437

love and prayers:
Andy,
i didn't find any clinical trials for beta thalassemia using JAK2 inhibitor but it is being used for other diseases.
is there a possibility that once it comes in the market, it could be used by thals?
some of the trials were in phase 2

Andy Battaglia:
Interesting question. I would say that once it's approved for other conditions, there may be doctors willing to try it for thal, even if it hasn't been trialed specifically for thal, just as there were doctors prescribing the Exjade/desferal combination as soon as Exjade was approved.

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