CAF Funds $375,000 in Important Thalassemia Research Areas
July 15, 2013 – What would motivate a person with thalassemia to make changes to improve adherence to therapy? Can metabolic substances in a person with thalassemia give a clue to how iron is loading in his/her heart? Would moving the fetal hemoglobin gene cause it to create more fetal hemoglobin?
These are just some of the questions that are being explored by the recipients of 2013-2014 CAF Medical Research Grants and Fellowships. All told, CAF will fund $375,000 in medical research through one Clinical Trial in Thalassemia Cell and Gene Therapy Grant, three Grants in Ongoing Clinical Research in Thalassemia and six Research Fellowships.
The recipients were selected by members of the CAF Scientific Review Committee, who evaluate applications on the basis of scientific content, the academic accomplishments and future promise of the investigator, the quality of the mentor (in the case of fellowships) and the relevance of the project to the understanding and treatment of thalassemia. The Committee made its recommendations for funding to the CAF Board of Directors, who approved those recommendations June 30 at its annual Board meeting.
“The Scientific Review Committee was very pleased with the high quality of the research proposed by CAF Fellowship Applicants this year,” says Ellis Neufeld, Chair of the CAF Medical Advisory Board. “The research supported by the Foundation is vital to the future of thalassemia care, from its basic science underpinnings to gene therapy approaches, to very important practical matters for patients, including nutrition and chelation adherence.”
Thalassemia Cell and Gene Therapy
CAF approved funding for a second year Thalassemia Cell and Gene Therapy Grant to Michel Sadelain, MD, PhD, Memorial Sloan-Kettering, for his project, “A Phase I Clinical Trial of Lentiviral Mediated β-Globin Gene Transfer in Patients with Cooley’s Anemia.” This trial, which began treating patients in late 2012, will assess the safety of Dr. Sadelain’s gene therapy procedure, as well as measure the differences in the hemoglobin produced by patients before and after the procedure. (You can read more about Dr. Sadelain’s project here.) It will help provide information that leads us closer to knowing whether gene therapy can cure thalassemia in humans as it has done in animal models. CAF is excited to be one of the funders of this study; the Foundation will be closely watching the results of this trial and other gene therapy thalassemia trials currently in development.
Ongoing Clinical Research in Thalassemia
CAF approved funding for one new and two renewal applications for 2013-2014.
What would motivate a person with thalassemia to make changes to improve adherence to therapy? Iron overload is a major concern in thalassemia, so finding ways to ensure that a patient sticks to his/her iron chelation therapy is extremely important. Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, will work on this question in her study, “Self-efficacy and adherence with iron chelation therapies in thalassemia.” Dr. Treadwell will use motivational interviewing, a technique which aims to understand from the patient what factors might affect his/her adherence and to improve the patient’s confidence in making changes that would improve adherence. Finding strategies that will help patients with their treatments is an area of great importance to CAF.
Think much about zinc? Ellen Fung, PhD, RD, CCD, Children’s Hospital & Research Center Oakland is thinking about its possible effect in people with thalassemia in the final year of her study, “Iron Overload, Zinc Status and Glucose Regulation in Patients with Thalassemia.” People with thalassemia often have a hard time getting enough zinc; Dr. Fung is looking into how this affects their blood sugar levels. (Dr. Fung’s presentation on “Recommendations for Dietary Intake” from the 2012 CAF Patient~Family Conference can be viewed here.)
Now that the U.S. has two oral chelators available, many patients wonder whether there might be a benefit in taking both of them. Janet Kwiatkowski, MD, MSCE, Children’s Hospital of Philadelphia, is conducting a “Pilot Study of Deferasirox and Deferiprone Combination Oral Chelation for Individuals with Transfusion Dependent Thalassemia and High Iron Burden.” The study will investigate whether the use of the two chelators together is safe and effective in thalassemic individuals with very high iron overloading.
Five new fellowships were approved for 2013-2014, joining one renewal fellowship.
Can metabolic substances in a person with thalassemia give a clue to how iron is loading in his/her heart? Farzana Sayani, MD, FRCPC, University of Pennsylvania, will be looking at that question in her project, “Metabolomics biomarker profiles to predict cardiac disease in transfusion-dependent beta-thalassemia.” Metabolites are metabolic substances, such as amino acids and vitamins. A “profile” of a person’s metabolites has been studied in non-thalassemic individuals; in these studies, a person’s metabolic profile has been shown to predict cardiac-related outcomes. Dr. Sayani will study metabolic profiles specifically in people with thalassemia and see what it might tell us about cardiac disease and cardiac iron.
Would moving the fetal hemoglobin gene cause it to create more fetal hemoglobin? Jeremy Rupon, MD, PhD, Children’s Hospital of Philadelphia is investigating this possibility in his project, “Augmenting γ-globin transcription via forced chromatin looping.” Using mice, Dr. Rupon will force the beta-globin gene to move closer to an element that is known to “activate” the gene. Will this result in the mouse creating a significant amount of fetal hemoglobin? We will be waiting to see what this study reveals to us.
Science has known for some time that the globin gene defect that causes thalassemia leads to abnormal red cell production in bone marrow, but there’s still a lot to learn about exactly how and why this happens. Hemant Kini, PhD, University of Pennsylvania, has a project entitled “Mechanism of PABPC4 action regulating terminal erythroid differentiation” that will look at one possible reason.
Whether two is better than one depends on a lot of things. What would happen if you tried two different iron overload treatments in thalassemic mice? Carla Casu, PhD, Weill-Cornell, is going to test this out via her study, “Novel approaches to treat iron overload in thalassemia.” Many thalassemia patients know one of these treatments very well: iron chelation therapy. The other involves increasing the amount of hepcidin, a hormone that affects how much iron is absorbed. In theory, combining the two should have a beneficial effect; this study will test that theory.
Some people with a very rare variant of alpha thalassemia don’t have a defect in the alpha genes; instead, a defect in in another gene “turns off” the alpha gene. Shigeki Iwase, PhD, University of Michigan, will explore this curious situation in his project, “Variable number tandem repeats and heterochromatin in α-thalassemia.”
If a person with thalassemia produces a greater amount of fetal hemoglobin, it makes his/her thalassemia less severe. What are some of the things that account for a higher or lower level of fetal hemoglobin? Laurie Steiner, MD, University of Rochester is in the second year of her project, “Detailed Genomic and Functional Analysis of the β-Thalassemia Modifier Genes BCL11a and HSB1L-MYB,” which is examining this question by looking at two genetic regions that may play a role in fetal hemoglobin expression.
CAF thanks all of the dediated doctors who served on this year’s Scientific Review Committee and congratulates all the 2013-2014 grant and fellowship recipients.
Special thank you to Ellis Neufeld for providing information for this article.