CAF Approves $720,000 in Research Grants

Funding medical research is one of CAF’s biggest priorities. Our medical research fellowship program has been encouraging and assisting promising researchers for decades; more recently, our grants for translational research in adult thalassemia have allowed us to expand into new areas of concern to the thalassemia community.

This year, CAF approved 6 grants in translational research and 9 medical research fellowships, amounting to $720,000 in medical research funding for the July 1, 2008-June 30, 2009 period. CAF is pleased to announce that the American Hellenic Educational Progressive Association (AHEPA) is once again partnering with CAF to fully fund one of the translational research grants and that the Long Island chapter of CAF has pledged financial support in the amount of $50,000 for a second. In addition, both The Child Reach Foundation and UNICO have each agreed to take on a CAF-approved medical research fellow and provide full and direct funding for these two fellows.

The medical research fellowships are awarded to post doctoral and junior faculty members investigating clinical or basic research related to thalassemia. Each fellowship carries an annual stipend of $40,000 and is awarded for one year, with the possibility of renewal for a second year.

Translational research grants are awarded to junior and senior faculty who interact directly with patients or patient-related data. Each grant carries an annual stipend of $60,000 and is awarded for one year, with the possibility of renewal for a second year.

At its annual Board meeting on April 26, 2008, CAF awarded six first-year and four renewal medical research fellowships and two grants in translational research. CAF is also currently funding the second year of its initial translational research grant.

Renewal grants in translational research was awarded to:

Derek A. Persons, MD, PhD, St. Jude Children’s Research Hospital, “Hematopoietic Stem Cell Gene Therapy for Beta-Thalassemia using Foamy Viral and Lentiviral Gamma-Globin Vectors”
(Funding for Dr. Persons’ grant has been provided by AHEPA.)

Sylvia T. Singer, MD, Children’s Hospital and Research Center, Oakland, “Fertility in Females with Thalassemia Major: Determination of Reproductive Status and Relation to Iron Overload”
(Click here for information about Sylvia T. Singer and her project.)

John C. Wood, MD, PhD, Children’s Hospital Los Angeles, “MRI diagnosis of preclinical diabetes in adult thalassemia patients”
(Click here for information about John C. Wood and his project.)

First year grants in translational research were awarded to:

Thomas M. Ryan, PhD, University of Alabama at Birmingham, “Induced Pluripotent Stem Cell Therapy for Cooley’s Anemia”

Michel Sadelain, MD, PhD, Memorial Sloan-Kettering Cancer Center, “A Phase I Safety Trial of Lentiviral Mediated β-globin Gene Transfer in Patients with Cooley’s Anemia”
(Funding for Dr. Sadelain’s grant in the amount of $50,000 has been provided by the Long Island chapter of CAF.)

Patrick B. Walter, PhD, Children’s Hospital & Research Center Oakland, “Dysregulation of the Innate Immune Response in Thalassemia Major: a Possible Mechanism for Increased Infection Risk”

Recipients of renewal fellowships for 2008-2009 include:

Faith Harrow, PhD, National Human Genome Research Institute, “Novel vectors for Cooley’s Anemia Gene Therapy Using Globin Regulatory Elements”

Seigo Hatada, PhD, University of North Carolina at Chapel Hill, “Targeted gene correction in multipotent hematopoietic cells”

Michela Battista, PhD, Mount Sinai School of Medicine, “Neuronal regulation of Hematopoietic stem and Progenitor Cells Mobilization”
(UNICO is providing direct funding for Dr. Battista’s fellowship.)

Rajasekhar Suragani, PhD, Massachusetts Institute of Technology, “Heme regulated eIF2alpha kinase signaling pathway: Potential for novel therapeutic compounds against beta-thalassemia”

Laura Breda, PhD, “Preclinical Test for Gene Therapy of β Thalassemia,” Weill Medical College of Cornell University

First year fellowships were awarded to:

Bindu Kanathezhath, MD, Children’s Hospital & Research Center Oakland, “Improving donor chimerism after major histocompatability complex mismatched transplant of umbilical cord blood cells with photochemically treated adult T lymphocytes in murine thalassemia”

Naoshi Obara, MD, PhD, “Functional Analysis of the DRED Repressor: Search for Ligands and Validation of Co-repressor Complexes,” University of Michigan Medical School

Karin Elisabeth Finberg, MD, PhD, “The Role of TMPRSS6 in Systemic Iron Homeostasis,” Duke University Medical Center

Dhvanit I. Shah, PhD, “Analysis of Genes Responsible for Erythropoiesis and Their Relevance to Congenital Anemias,” Brigham and Women’s Hospital & Harvard Medical School

CAF congratulates all of these recipients and thanks them for their commitment to thalassemia research.

Information About Recipients and Projects

Derek A. Persons
Derek A. Persons received an MD from the Duke University School of Medicine, Durham, North Carolina and a PhD from the Duke University Graduate School, Durham, North Carolina. He is currently an assistant member of the faculty at St. Jude Children’s Research Hospital (hematology department), where his interests include gene therapy for hemoglobin disorders and hematopoietic stem cell biology.

Description of Work
The gene therapy treatment option for Cooley’s anemia will offer patients a curative therapy different from that of stem cell transplantation, which utilizes the cells of another individual. This strategy eliminates the risks associated with transplantation of cells from another person. We previously developed a lentiviral vector system to transfer the γ-globin gene into the chromosomes of hematopoietic stem cells of mice and primates. This vector was successful in correcting β-thalassemia in mice by producing high levels of fetal hemoglobin (formed by the γ-globin protein) in the red blood cells. Our proposed research will compare our lentiviral γ-globin vector system to a system based on the non-disease causing foamy virus. Foamy virus vectors were developed by our collaborator, Dr. David Russell, over the past decade and have potential advantages over the lentiviral vector system. Here we propose to evaluate these possible advantages in efficacy and safety using cells from Cooley’s anemia patients. Bone marrow stem cells from patient volunteers will be treated with the viral vectors in the laboratory and then transplanted into a special strain of mice which allows them to grow and develop into red blood cell precursors. We will directly compare the two vector systems for performance and safety in this model. These studies will be important in helping decide which system should be used to treat Cooley’s anemia patients.

Sylvia Singer
As a Hematology/Oncology physician at CHRCO, I have centered my career interests over the past seven years on thalassemia, at both a clinical and a research level. Working with an internationally recognized expert in pediatric hematology, Dr. Elliott Vichinsky, I have been able to combine my clinical efforts and research interests on this prevalent and complex disease. My first project involved investigating the frequency of alloimmunization and autoimmune hemolytic anemia in chronically transfused thalassemia patients. I then moved to coordinate the NIH funded study on a significant, yet under-recognized type of thalassemia: Hemoglobin E/beta-thalassemia (RO1 HL-97-013) from 1998-2003. < br />
Currently I am funded to investigate the risk factors for developing pulmonary hypertension in thalassemia (1 K23 HL077409-01A1). By integrating basic science in coagulation/inflammation with clinically significant complications in thalassemia, I hope to contribute to this field and to improve the outcome of thalassemia patients. My short term goals include continuing to investigate this topic and identifying markers for developing a larger randomized study for identifying and treating hypercoagulable problems and pulmonary hypertension in thalassemia. My future goals continue to center around developing a career in clinical and translational research of thalassemia.

I actively participate in the thalassemia clinics and am mostly interested in addressing and developing research centered on clinical problems that affect patients. Through my current research, I expect to transition into an independent clinical investigator and to be able to execute such studies.

Description of Research
Infertility and early menopause are among the most difficult issues for adult females with thalassemia major, who are now living longer lives. Newer tests to assess the chances of women getting pregnant are now available, but have not yet been tested in thalassemia females. These include blood tests and a special ultrasound of the ovaries. In this study, we propose to use these methods with 16-18 adult thalassemia major females in order to be able to predict their chances for pregnancy and determine their fertility status. We would then assess how the level of iron overload and toxic effects of iron are related to their fertility. This could provide a better understanding of the reasons for, and the timing in which, this damage to the reproductive system occurs. With further study, these methods could become an important way to find out fertility status and how it relates to the level of iron overload. It may lead to earlier treatment intervention for preserving fertility, which can have a profound impact on patients’ quality of life.

John Wood
Dr. John Wood graduated from UC Davis (Electrical Engineering) in 1984 and received his MD/PhD (Bioengineering) from the University of Michigan in 1994. He performed his residency and fellowship in Pediatric Cardiology at Yale and joined Children’s Hospital Los Angeles/USC Keck School of Medicine in 1999. Dr. Wood is the director of cardiovascular MRI and specializes in the MRI assessment of congenital heart disease, as well as noninvasive assessment of iron burden by MRI.

Dr. Wood has been studying the cardiovascular consequences of hemoglobinopathies for almost a decade. He is one of the pioneers of MRI-based cardiac and liver iron measurements but is also studying oral chelation strategies in animals and humans. He is the principle investigator for the NIH-sponsored Early Detection of Iron Cardiomyopathy Trial, which is trying to identify earlier markers of cardiac dysfunction. Dr. Wood has recently begun studying the relationship between pancreatic iron burden by MRI and their functional correlates.

Description of Research
Diabetes is common in thalassemia major and becoming more important as patients live longer. Standard patient monitoring for diabetes detects disease only once it is fairly advanced and not completely correctable. We believe that magnetic resonance imaging (MRI) can be used to detect iron in the pancreas before irreversible damage is present and can be used to guide iron removal therapies. This study will examine the relationship between MRI detectable iron in the pancreas and liver with tests of pancreas function and sugar metabolism in thalassemia patients.

Thomas M. Ryan
Thomas M. Ryan (b. 1956) received B.A. degrees in Biology and Chemistry from Humboldt State University (Arcata, CA, 1982). Dr. Ryan received his Ph.D. in Microbiology in 1990 from the University of Alabama at Birmingham for his studies on human globin gene expression, synthesis, and switching in transgenic mice. These studies defined the functional importance of regulatory sequences in the locus control region of the human beta globin locus. Linkage of these sequences to the human alpha, gamma, and beta globin genes enabled the production of the first transgenic animals that synthesized functional human hemoglobin and the first demonstration of human fetal to adult hemoglobin switching. Post-doctoral research (1991-96) in the Biochemistry Department at the University of Alabama at Birmingham in the laboratory of Tim Townes led to the development of the first animal models of beta thalassemia and sickle cell disease. Continuing these studies in the Biochemistry and Molecular Genetics Department as a Research Assistant Professor (1997-2003), Dr. Ryan produced the first knockout-transgenic animal model of sickle cell disease. Dr. Ryan became an Assistant Professor in Biochemistry and Molecular Genetics in 2003 and served as the Graduate Program Director from 2004 to 2007. Dr. Ryan’s laboratory is currently working on experimental stem cell therapies for human disease with a focus on Cooley’s Anemia.

Description of Research
Thalassemia is one of the most common genetic disorders worldwide. Cooley’s anemia, the most severe form of β thalassemia, is characterized by the complete absence of the β-globin polypeptide chains of hemoglobin in red blood cells. The main objective of this proposal is to model a stem cell based therapy for Cooley’s anemia. Retroviral gene therapy will be utilized to reprogram adult cells into less differentiatied pluripotent stem cells for use in therapy. Human and thalassemic mouse fibroblasts will be reprogrammed in these studies. The induced pluripotent stem (iPS) cells produced will be compared to embryonic stem (ES) cells in their ability to form teratomas or generate chimeric animals after their introduction into mouse blastocysts. These iPS cells will be differentiated in vitro into pure erythroid progentitor cells for transplantation. This project will test if early erythroid progenitor cell therapy can replace standard red blood cell transfusions in thalassemia, thereby minimizing the amount of exogenous iron introduced into the body with repeated transfusions. A novel preclinical humanized animal model of Cooley’s anemia will be utilized for these in vivo studies. These mice survive solely on human fetal hemoglobin at birth and are blood transfusion dependent for life upon completion of their hemoglobin switch after birth. Successful completion of these studies will outline a general strategy, whereby erythroid progenitor cells derived from corrected patient-specific iPS cells could be used for the treatment of Cooley’s anemia.

Michel Sadelain

Dr. Sadelain’s research focuses on stem cell and T cell engineering. He has been studying globin gene transfer for the treatment of β-thalassemia for the past 17 years. In 2000, he reported how to successfully treat thalassemic mice using lentiviral-mediated globin gene transfer. In 2007, his proposal to test this treatment in patients with β-thalassemia major was approved by the RAC. This trial is likely to be the first trial in the US utilizing a complex, tissue restricted lentiviral vector for the treatment of a congenital blood disorder and the first clinical investigation of globin gene in a severe hemoglobinopathy. He is the incumbent of the first Stephen and Barbara Friedman chair and was recently named the founding director of the Center for Cell Engineering at Memorial Sloan-Kettering Cancer Center. He is fully committed to pursuing research on a genetic treatment of β-thalassemia.

Description of Work
Cooley’s anemia is caused by a mutation in the β-globin gene, which results in reduced production of the protein β-globin.

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