CAF Awards $260,000 Funding in Medical Research Fellowships

July 10, 2017– CAF is pleased to announce that five new Cooley’s Anemia Foundation Medical Research Fellowships and three renewal Fellowships have been awarded for the 2017-2018 grant cycle. The total amount of funding for the 8 research Fellowships is $260,000.

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 Grant 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, former 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.

Nikoleta Psatha, PhD, of University of Washington in Seattle, will conduct research in gene editing through her study, “Two innovative approaches for genome editing in beta-thalassemia.” In the first approach she will produce simultaneously two fetal hemoglobin activating events in one genetic vector designed for two genomic targets with a CRISPR/Cas9 Nuclease approach. This should increase the formation of HbF and theoretically would provide additional benefit for patients undergoing gene editing therapy. In the second approach, she aims to develop gene therapy constructs with the use of non-integrating adenoviral vectors, to facilitate an efficient delivery to patient. The significance to thalassemia is high. Only a third of patients have a suitable donor and approaches to modify stem cells are a possible way to a cure.

Antonella Nai, PhD, of San Raffaele University in Milan, Italy, will be examining whether TfR2 (a gene mutated in the iron overload disorder, hereditary hemochromatosis) expression in red blood cells of wild type and thalassemic mice can increase red blood cell number in the short term. Dr. Nai will use a number of approaches to inhibit TfR2 activity in the developing red blood cells of a thalassemic mouse model through her study, “Transferrin Receptor 2 : A Novel Potential Therapeutic Target for B-Thalassemia.” In collaboration with Ionis Pharmaceuticals, Inc., Dr. Nai will test the use of antisense oligonucleotides (ASOs), to reduce TfR2 expression in developing red blood cells. Prior work from Drs. Nai and her mentor, Dr. Clara Camaschella, using the genetic approach of deleting TMPRSS6 in thalassemic models is ready for phase I clinical trials, demonstrating the success of this team in the identification and validation of clinically relevant targets for thalassemia.

Lei Yu, PhD, of University of Michigan Medical School, will be focusing on development of a small molecule analog to inhibit the activity of a repressor complex of fetal globin expression through his study, “Development of RN-1 Analogs to Inhibit LSD1 Activity as a Strategy to Treat B-Thalassemia.” This study builds on fine-tuning a molecule that has already shown high promise in pre-clinical models; hence it is already closer to clinical application and thus merits the efforts to optimize its properties. Appropriate, in-house collaborations on pharmacology and efficacy have also been set up and thus increase confidence in the ultimate success of the approach.

Daniel Lucas, MD, PhD, of University of Michigan Medical School, will conduct a set of studies proposed to improve hematopoietic reconstitution (recovery of the bone marrow and its environment) after hematopoietic stem cell transplantation. Preliminary data from both well-controlled mouse experiments and retrospective analysis of data from human thalassemia patients who have undergone transplant suggests that time to marrow recovery and avoidance of “graft failure” can be improved as the number of bone marrow-derived granulocytes increases. Dr. Lucas’s study, “Identification of the cellular targets through which granulocytes drive hematopoietic regeneration after transplant,” is well suited to determine both the role of TNF-alpha in this process and its potential cellular target in the perivascular niche. This work has tremendous potential to help advance hematopoietic stem cell transplantation, particularly when limited donor cells are available.

Julia Xu, MD, of Duke University, aims to understand understand the beliefs, attitudes, and behaviors of Myanmese and Lao migrant populations towards thalassemia in her study, “Thalassemia Screening in Myanmese and Lao Migrants in Thailand.” Little is currently known about perceptions of blood disorders, inherited diseases, and prenatal testing in these vulnerable populations where thalassemia is highly prevalent. The information obtained from these studies can be used to develop thalassemia screening and prevention programs, targeted education, and health care programs for this population. Given the large burden of thalassemia in Thailand and Southeast Asia and changing migration patterns, with increasing numbers of immigrants from these regions to the United States, the knowledge gained from this grant should have a significant global impact, aiding in the development of culturally-appropriate screening programs and health care delivery.

Renewal Fellowship Recipients

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 has made excellent progress in Year 1 and in Year 2 she will carrying out rigorous testing of this approach in a well-defined thalassemia population. 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.”

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.”

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. In the first year she has completed the first phase successfully and she proposes to next determine how this protein acts in the liver to regulate iron homeostasis in mice.

“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.”


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