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September 27, 2016- CAF is pleased to announce that four new Cooley’s Anemia Foundation Medical Research Fellowships and one renewal Fellowship have been awarded for the 2016-2017 grant cycle. In addition, this year we have awarded a new Clinical Research Grant to support ongoing clinical research in thalassemia. The total amount of funding for the five research Fellowships and one Clinical Research Grant for the current cycle is $202,500.
These Fellowship recipients were assessed on the basis of the quality of the scientific content, the academic accomplishments and future promise of the investigator, the quality of the mentor in the case of postdoctoral fellowships, and, of particular importance, the relevance of the project to the understanding and treatment of Cooley’s anemia. The CAF Scientific Review Committee reviewed all applications carefully while adhering to the highest standard for scientifically un-biased reviews and made its recommendations for funding to the CAF Board of Directors, who approved those recommendations at its annual Board meeting.
Dr. Ellis Neufeld, Chair of the CAF Grant Review Committee and Medical Advisory Board, says, “This year’s CAF Fellowships cover the very broad range of scientific and clinical topics of interest to the thalassemia community. These are cutting-edge investigations, extending from genomics and prenatal diagnosis to iron metabolism to red blood cell development to clinical studies, to fulfilling the promise of gene therapy. We are excited to see what the investigators learn in these important experiments. “
First Year Fellowship Recipients
The following individuals have been awarded new Fellowships for this grant cycle. Fellowships are awarded for one year with renewal for a second year contingent upon review of progress.
Katie Carlberg, MD, of the Children’s Hospital Oakland, is developing a noninvasive approach to prenatal diagnosis of thalassemia in her study, “SNP Discovery and Characterization of the Human Beta-Globin Gene for Non-Invasive Prenatal Testing for Beta-Hemoglobinopathies.” Current approaches to prenatal diagnosis of thalassemia are invasive and increase risk of morbidity to mother and fetus. This noninvasive approach is based on recent advances in DNA isolation and enrichment and DNA sequencing, and could be accomplished as early as 8 weeks of gestation. Dr. Carlberg’s research will establish a critical experimental foundation to developing a cutting-edge major advance in this field.
“Thalassemias are some of the most common autosomal recessive (AR) disorders in the world,” Dr. Carlberg explains. “The development of non-invasive prenatal testing (NIPT) for AR disorders has proven challenging as it requires knowing which allele was transmitted to the fetus from each parent… We will investigate an indirect method that involves calculating the ratio of sequence reads for the two maternal beta-globin alleles and compareing this ratio from the maternal plasma DNA to the maternal whole blood DNA.”
Karen Finberg, MD, of Yale Medical School, is studying the process of how the gene NCOA4 mediates the degradation of ferritin in her study, “The Role of NCOA4 in the Regulation of Hepatic Iron Stores.” She will be using mouse strains exhibiting different extremes of iron regulation to conduct her experiments. Her findings could prove that increasing NCOA4 could accelerate the removal of excess iron from the liver, which then would be removed by chelation therapy.
“How iron is released from the body’s storage sites… is currently very poorly understood,” says Dr. Finberg. “In this study, we plan to use mouse models and cultured cells to investigate the biological processes that enable iron to be removed from the liver, the body’s major organ of iron storage. It is our hope that our research findings will contribute to improved clinical outcomes for patients with b-thalassemia by providing knowledge that will aid in the development of new therapeutic approaches to promote iron removal from the body.”
Merlin Nithya Gnanapragasam, PhD, of Icahn School of Medicine at Mount Sinai in New York City, is performing experiments in HuDEP-2 cells to examine the consequences of mutation of the EKLF upstream enhancer region in her project, “Genome Editing of EKLF Enhancer Elements for Fetal Homoglobin Induction.” She will also be experimenting with homology directed recombination of JMML intron enhancer mutation into human erythroid progenitor HuDEP-2 cells to test the effect on erythroid differentiation and globin gene expression.
“Beta thalassemia is one of the most common inherited disorders,” Dr. Gnanapragasam explains. “An attractive therapeutic strategy to ameliorate and potentially cure beta thalassemia is to increase fetal hemoglobin levels in the red blood cells of people who have thalassemia. Erythroid Kruppel Like Factor (EKLF/KLF1) is a transcription factor that is essential for the proper regulation of hemoglobin genes. My goal is to identify strategies to increase fetal hemoglobin levels, by modulating EKLF’s regulation of globin gene expression using genome editing.”
Kim Vanuytsel, PhD, of Boston University, is studying ineffective erythropoiesis and iron regulation in beta thalassemia using induced pluripotent stem cells in her study, “Induced Pluripotent Stem Cell (Ipsc)-based Modeling of Beta Thalassemia.” This project involves developing new models for ineffective erythropoiesis and iron regulation using stem cells generated from research subjects with beta thalassemia. If successful, this work could have considerable impact due to the potential for application toward many aspects of the pathogenesis and treatment of beta thalassemia.
“Beta thalassemia patients, in addition to developing anemia, suffer from systemic iron overload, which leads to long-term organ damage and is a major focus of therapeutic management,” says Dr. Vanuytsel. “This [fellowship] will provide an unprecedented opportunity to study this multisystem disorder in a human setting and at the same time presents a valuable tool for testing new diagnostic approaches and therapeutic strategies targeting hepcidin dysregulation and the resulting systemic iron overload in beta thalassemia patients.”
Renewal Fellowship Recipient
Daniel Bauer, MD, Children’s Hospital Boston, is investigating how genome editing may be useful in creating greater expression of fetal hemoglobin in adult thalassemia patients in his project, “Genome Editing of Beta-Globin Gene Cluster Repressive Elements for Beta-Thalassemia.” He has made considerable progress during the first year of the fellowship, and these continued experiments are intended to enable the development of clinical trials of therapeutic genome editing for B-thalassemia.
“Over the past few years there has been an unprecedented explosion in our understanding of various areas of basic science, including in human genetics, gene regulation, and genome editing,” says Dr. Bauer, “together these advances make curative treatments for genetic disorders like thalassemia increasingly realistic.”
Clinical Research Grant
Nathawat Sibmooh, MD, PhD, of Mahidol University in Bangkok, is investigating the issue of immediate treatment for thalassemia patients who have developed pulmonary hypertension in his study, “Effect of inhaled, nebulized nitrite on pulmonary arterial pressure in beta-thalassemia patients with pulmonary hypertension.” Hypertension can be a cause of severe morbidity and even death, especially amongst non-transfusion dependent beta thalassemia patients, usually adults, and particularly those who have had splenectomy. This trial is very relevant to treatment of pulmonary hypertension in lower-resource areas of the world where thalassemia is highly prevalent and the cause of death for many young adults.
Dr. Simbooh reports that “thalassemia patients have nitric oxide deficiency leading to abnormal constriction of blood vessels, thrombosis, pulmonary hypertension, and heart disorders.” His goal is to find new treatment for pulmonary hypertension in thalassemia, and says “this research will lead to development of nitrite as a drug for treatment of pulmonary hypertension in thalassemia. Because of its immediate and short action, nitrite can be used at least in rescue therapy during exacerbation of pulmonary hypertension such as exercise-induced symptoms. Due to the antiproliferative and anti-inflammatory effects of nitric oxide, long-term nitrite therapy may be able to slow a change in lung tissue (remodeling) or delay progression of pulmonary hypertension as well.”
The Cooley’s Anemia Foundation congratulates this year’s recipients and is proud to support their important work in thalassemia research.