New Treatment and a Cure for Thalassemia and Sickle Cell Anemia

Hi there

I found this from the Children's cancer and blood foundation:


On the Research Front - New Treatment and a Cure for Thalassemia and Sickle Cell Anemia


Dr. Stefano Rivella, Associate Professor of Genetic Medicine, has been working on groundbreaking research in gene transfer therapy, in which damaged genes are corrected by transferring healthy genes. As a result of this technique, we have successfully cured beta-thalassemia (more commonly known as Cooley's anemia) in the laboratory and are confident that this system will be beneficial for sickle cell patients as well.

In other developments, Dr. Rivella and his colleagues have discovered a way to avoid removing the spleen in patients suffering from beta-thalassemia. Dr. Rivella has been working with JAK2 inhibitor, which blocks the expression of the JAK2 gene. In Cooley's anemia, this gene is highly expressed and is thought to play a crucial role in the malformation of red blood cells. When this gene has been mutated, the spleen may become enlarged and the patient is at risk for blood clotting. JAK2 inhibitor has been shown to successfully shrink spleens to normal sizes and ameliorate the production of red blood cells in tests.


Dr. Rivella will be starting clinical trials for these new developments, but needs additional funding for the development of drugs necessary to successfully move ahead.  Help Dr. Rivella with his important research by donating now!

 
Jade
 
 

Dr. Rivella and his colleagues may have found a way to avoid removing the spleen in patients suffering from beta-thalassemia.  The spleen filters unhealthy cells protecting the body from harm, but in many patients, it must be removed in order to prevent potentially fatal complications. Once the spleen is removed, patients are at a greater risk for stroke and infection.  Dr. Rivella has been working with JAK2 inhibitor to prevent splenectomies for patients.  JAK2 inhibitor blocks the expression of the JAK2 gene, which helps the body signal pathways to generate blood cells.  In Cooley’s anemia, this gene is highly expressed and is thought to play a crucial role in the malformation of red blood cells.  When this gene has been mutated, the spleen may become enlarged and the patient is at risk for blood clotting.  JAK2 inhibitor, currently in human trials for the treatment of myelodysplastic leukemia, has been shown to successfully shrink spleens to normal sizes and ameliorate the production of red blood cells in tests.

Thank you Jade, this is very interesting. 

Andy, would this benefit beta zero thals?  Can it be effective for thals have AIHA?

Thank you,

Sharmin

  Jade for the info.

Zaini.

By suppressing the JAK2 gene, the researchers have been able to return normal function to the spleen. While the focus of this research has been to find a method of avoiding splenectomy, it had the somewhat unexpected consequence of reducing ineffective erythropoiesis (IE). Beta thalassemia is a complicated disorder that involves more than just not producing enough good red blood cells. The production of deficient red cells is also a problem that causes many of the problems associated with thalassemia. By reducing IE, a positive effect was seen on Hb levels.

This is very interesting and I think it would have some application even in thal beta zero, although more likely in terms of less destruction of red blood cells by the spleen. I don't want to say for sure that it would have an effect on AIHA, but returning the spleen to normal function may have some effect. This is a lot to absorb and has given the researchers much to think about in terms of what this means outside of the obvious restoration of normal spleen function.

The abstract can be seen at http://news.med.cornell.edu/wcmc/wcmc_2008/05_22_08.shtml

Avoiding Spleen Removal for Cooley's Anemia Sufferers


Weill Cornell Researchers May Have Identified Gene Responsible for Mutated Red Blood Cells


Preclinical Study Provides Fresh Perspective on Disease, with Potential New Therapeutic Options


NEW YORK (MAY 22, 2008) — 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 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.


Disease Background

Mutations in the beta globin gene can lead to thalassemia or sickle-cell anemia. Thalassemia and sickle-cell anemia are quite common, not only in Mediterranean, but also in African, African-American, and Asian populations; however, specific sets of mutations are associated with different ethnic groups. It has been estimated that approximately seven percent of the world population are carriers of such disorders, and that 300,000-400,000 babies with severe forms of these diseases are born each year.

Beta-thalassemia, one of the most common of the congenital anemias, is due to partial or complete lack of synthesis of beta-globin chains. Cooley's anemia, also known as beta-thalassemia major, the most severe form of this disease, is characterized by ineffective erythropoiesis (IE) and extra medullary hematopoiesis (EMH), requiring regular transfusions to sustain life. In beta-thalassemia intermedia, where a greater number of beta-globin chains are synthesized, the clinical picture is milder, and patients do not require frequent transfusions. However, hemoglobin (Hb) levels often decrease over time, splenomegaly appears, and progressive iron overload occurs from increased gastrointestinal iron absorption.

Despite its prevalence, Cooley's anemia (beta-thalassemia) is an orphan disease, of which studies are rare and not well-funded. Current disease management includes prenatal diagnosis, transfusion therapy, iron chelation and allogeneic bone marrow transplantation (BMT). The hallmark of the disease is ineffective erythropoiesis (IE), which leads to erythroid marrow expansion to as much as 30 times the normal level. Extra-medullary erythropoietic tissues, primarily in the thorax and the paraspinal regions, can be stimulated to expand, leading to the characteristic deformities of the skull and face, osteopenia, and demineralization of the bones, which are then prone to fractures. Despite excessive erythropoietic activity, affected persons suffer from anemia, which is exacerbated by progressive splenomegaly and an increase in plasma volume as a result of shunting through the expanded marrow.


Splenectomy (Removal of Spleen)

After splenectomy, patients are considered immunocompromised, and so should be placed on lifelong prophylactic oral antibiotics. Patients should also be vaccinated against common viral infections, and should receive annual influenza vaccinations.

Researchers are still learning about the health effects that stem from years of living with reduced or deficient globin proteins. An emerging realization is that removal of the spleen can cause an increase in the risk of life-threatening blood clots. Splenectomy is common for thalassemia patients because their red blood cells are crippled or dead, so the spleen has to work overtime and can become enlarged.

Researchers disagree on the degree of risk associated with splenectomy. A study by Dr. M. Domenica Cappellini, a co-author of this research, found that 30 percent of splenectomized thalassemia intermedia patients developed clots. However, a recent study of 8,860 splenectomized patients with thalassemia major and thalassemia intermediate found that the rate of thrombolytic events was 1.75 percent.

Surgical technique has played a role in developing clots (thrombosis). A recent study found that patients who underwent open splenectomy had a 19 percent chance of developing life-threatening clots, whereas patients who had laparoscopic surgery had a 55 percent chance.

Researchers are only now discovering why splenectomy leads to clots. Injury of endothelial cells may lead to a coagulation cascade, involving the activation of endothelial adhesion proteins, monocytes, granulocytes and platelets. Alternatively, the splenectomy might result in an imbalance between coagulation factors and anticoagulation factors. Dr. Cappellini has recommended short-term anticoagulants such as heparin after surgery, and prophylactic anticoagulants any time thalassemic patients are exposed to thrombolytic risk factors such as surgery, prolonged immobilization or pregnancy. Oral contraceptives should be avoided because they carry their own risk of thrombosis.

This study was funded by grants from the National Institutes of Health (NIH), the Carlo and Micol Schejola Foundation, the Roche Foundation for Anemia Research (RoFAR), the Cooley's Anemia Foundation (CAF), the Children's Cancer and Blood Foundation (CCBF), the Associazione per la Lotta alla Talassemia di Rovigo (AVLT), and the American Portuguese Biomedical Fund.

Dr. Rivella's co-authors and collaborators include Drs. Ilaria Libani, Ella Guy, Luca Melchiori, Raffaella Schiro, Pedro Ramos, Laura Breda, Amy Chadburn, YiFang Liu, Matteo Porotto, Patricia Giardina and Robert Grady — all of Weill Cornell Medical College in New York City; Dr. M. Domenica Cappellini, as well as Dr. Libani, of Centro Anemie Congenite, the University of Milan; Dr. Maria de Sousa, as well as Dr. Ramos, of Iron Genes and Immune System (IRIS) Lab, Oporto University, Portugal; Drs. Thomas Scholzen, Margrit Kernbach, Bettina Baron-Luehr and Johannes Gerdes, of Research Center Borstel, Germany; Dr. Eliezer Rachmilewitz, of E. Wolfson Medical Centre, Israel; and Dr. John Hood, of TargeGen, Inc., San Diego.


About Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in areas such as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, transplantation medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries of the human body in health and sickness. In its commitment to global health and education, the Medical College has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. For more information, visit www.med.cornell.edu.

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Andrew Klein
ank2017@med.cornell.edu

A further update on the use of Jak2 inhibitors in thalassemia intermedia and major. This continues to show great promise for both transfusing and non-transfusing thals. By reducing the Jak2 inhibitor dose in intermedia mice, they were able to shrink the spleen without any drop in Hb level. In addition the use of the drug brings the spleen back to normal health and functionality, and also ameliorates the pathologic iron metabolism in thalassemia. This was one of several different approaches to thalassemia treatment that was presented at the NYC conference. Treatment for thalassemia will be greatly changed from what it is now within the next 20-25 years. I will keep saying this. These changes will be so dramatic, that a cure will not be so critical.

http://ash.confex.com/ash/2009/webprogram/Paper23729.html

Use of Jak2 Inhibitors to Limit Ineffective Erythropoiesis and Iron Absorption in Mice Affected by β-Thalassemia and Other Disorders of Red Cell Production
Oral and Poster Abstracts
Poster Session: Thalassemia and Globin Gene Regulation Poster I
Saturday, December 5, 2009, 5:30 PM-7:30 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board I-1042

Luca Melchiori1*, Sara Gardenghi, PhD1*, Ella C. Guy1*, Eliezer Rachmilewitz, M.D2, Patricia J Giardina, MD1*, Robert W. Grady, PhD1*, Mohandas Narla, DSc3*, Xiuli An, MD, PhD3 and Stefano Rivella, PhD1

1Weill Cornell Medical College, New York, NY
2Hematology, The Edith Wolfson Medical Center, Holon, Israel
3New York Blood Center, New York, NY


 β-thalassemia intermedia (TI) and major (TM) are characterized by Ineffective Erythropoiesis (IE). We hypothesized that the kinase Jak2 plays a major role in IE and splenomegaly. To test this hypothesis we administered a Jak2 inhibitor (TG101209) to mice affected by TI, showing that this treatment was associated with a marked decrease in IE, and a moderate decrease in hemoglobin (Hb) levels (~1 g/dL). This last observation indicates that the use of a Jak2 inhibitor might exacerbate anemia in thalassemia. However, we hypothesized that using standard transfusion to treat TM mice would also be adequate to prevent any further anemia caused by Jak2 inhibition while still allowing for decreased splenomegaly. Therefore, we analyzed the erythropoiesis and iron metabolism in TM animals treated with a Jak2 inhibitor and transfused. Use of TG101209 in TM  mice not only reduced the spleen size dramatically (0.42±0.15 g and 0.19±0.10 g  respectively in transfused+placebo (N=4) vs transfused+TG101209 (N=8), P= 0.007), but also allowed the mice to maintain higher Hb levels (respectively 7.3±1.1 g/dl vs 9.3±1.2 g/dl, P=0.019). This was likely due to reduced spleen size and limited red cell sequestration. Contrary to TM mice treated with transfusion+placebo, no foci of extra-medullary hematopoiesis were detectable in the parenchema of mice treated with TG101209. Hamp1 expression inversely correlated with the spleen weight, possibly indicating that suppression of IE (due both to blood transfusion and TG101209 administration) had a positive effect on Hamp1 expression. Hb levels also directly correlated with Hamp1  expression in the same animals. In this case, however, only transfusion played a role in increasing Hamp1 expression, although TG101209 undoubtedly had a positive effect by reducing the spleen size and thereby indirectly increasing the Hb levels.
The suppression of erythropoiesis by blood transfusion limits the extent of our interpretations as it may mask the effect of the Jak2 inhibitor. Therefore we hypothesized that the administration of a tailored and reduced dose of the drug could be effective in reducing the splenomegaly in non-transfused TI mice, without affecting the Hb levels. We also hypothesized that the suppression of erythropoiesis would also lead to increased Hamp1 expression in the presence of iron overload. Compared to mice treated with placebo (N=5), analysis of TI mice treated with a tailored dose of 100mg/kg/day of the drug (N=11) showed a significant decrease in spleen size (0.18±0.05 g and 0.27±0.05 g, P=0.006 for drug treated mice and placebo treated mice respectively). Of note no significant difference of Hb levels was detectable between the 2 groups. In the drug treated mice we observed a significant decrease of the immature erythroid cell population (P=0.012) and amelioration of the architecture of the spleen, with the reappearance of white pulp foci and a significant restoration of the splenic lymphocitic populations. Drug treated mice showed increased levels of Hamp1 mRNA that inversely correlated with the spleen weight, suggesting a direct feedback between erythropoietic rate and expression of Hamp1.
To determine if the use of Jak2 inhibitors could be beneficial in a mouse model mimicking a human form of hereditary ellyptocytosis, we treated mice KO for the 4.1R protein isoforms with TG101209, in presence or absence of blood transfusions. These mice exhibit moderate splenomegaly and anemia and the drug treatment was effective in reducing the spleen weight and the associated IE. We also plan to analyze Sickle Cell mice that we are treating with a Jak2 inhibitor. In conclusion our data show that the administration of Jak2 inhibitors is efficient in decreasing the spleen size and ameliorating the pathologic iron metabolism in thalassemia, both in the presence or absence of blood transfusions. Moreover we show that Jak2 inhibitors could transform the therapeutic approach for other forms of anemias.

A new application for Jak-2?!!!! great!!! what a valuable paper