Summary of Research Funded by the DBAF

Date Funded 6/19:

The DBAF awarded a grant for $50,000 to Dr. Lionel Blanc, PhD, who is at the Feinstein Institute for Medical Research in New York City, with co-investigator Dr. Jeffrey Lipton. The project is entitled, “Beyond the erythron, skeletal defects in Diamond Blackfan anemia.” The overall goals of this research are (1) to understand the defects in bone development (poor linear growth, osteopenia, skeletal anomalies) as a consequence of RP haploinsufficiency (2) to acquire a fuller understanding of the etiology of osteogenic sarcoma in the context of DBA, and thus (3) to determine the role of ribosomal protein gene mutations in oncogenesis, using DBA as a model. These studies by two leaders in the field will advance our knowledge of the effects of ribosomal protein haploinsufficiency on bone development and also create a model system for studying carcinogenesis that promises to increase our understanding of how ribosomal protein insufficiency increases the risk for solid tumors.

Date Funded 3/19:

Kathleen Sakamoto M.D., Ph.D., a professor in the School of Medicine at Stanford University, received a grant for $62,409 with support from DBA Canada and Friends of DBA. The project is entitled “Targeting Nemo-like Kinase for the Treatment of Diamond Blackfan Anemia.” The goal of this research is to examine the signaling pathways regulating mTOR activity as a consequence of Nemo-like kinase (NLK) inhibition in models of Diamond Blackfan Anemia. If these results are confirmed, it would suggest that inhibition of this kinase could be an effective therapeutic intervention for treating the bone marrow failure associated with DBA.

Date Funded 12/18:

The DBAF and DBA Canada proudly increased DBA awareness among attendees at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition held in San Diego. The event was attended by over 20,000 worldwide hematologists, researchers and other health-related professionals. Visitors to the DBA booths received information regarding DBA clinical care, patient opportunities, and research.

Date Funded 12/18:

The DBAF has awarded $54,754 with support from DBAC and from Friends of DBA to Dr. Scott C. Blanchard, PhD, from Weill Cornell Medicine for the project entitled “Identifying associations between DBA and genomic variation in ribosomal DNA”. The overall aims of the proposal are to sequence the ribosomal DNA (rDNA) repeat to assess whether sequence variation within this repeat contributes to the clinical features of DBA. This is a novel approach to understanding clinical variability among DBA patients.

Date Funded 3/18:

The 15th Diamond Blackfan Anemia International Consensus Conference was held March 10-12 at the Ritz-Carlton Hotel in downtown Atlanta, Georgia. The overriding goal of this and past ICC meetings has been to identify therapies and strategies to improve the quality of life for patients and families with DBA.

Date Funded 2/18:

Johan Flygare, M.D., Ph.D. of Lund University in Sweden was awarded $75,000, with support from DBA Canada and Friends of DBA, for his project entitled, “Targeted corticosteroid therapy for DBA.” The goal of the proposal is to enhance the delivery of steroids directly to erythroid progenitors in DBA to reduce the overall toxicity of steroids, which often limits their effectiveness as a treatment for DBA. The approach Dr. Flygare will use is to attach steroids to an antibody that specifically recognizes a protein expressed on erythroid progenitors. After binding to the erythroid progenitors, the antibody gets internalized, delivering the steroids specifically to only those cells that are recognized by the antibody. Using this approach, one could presumably lower the amounts of steroids used to get a beneficial effect, and since the delivery is specific, it would reduce the amounts of steroids hitting other tissues causing side effects.

Date Funded 1/18:

The DBAF awarded a grant for $15,000 to Dr. Steve Ellis, Ph.D. at the University of Louisville to continue to provide experimental services to clinicians and scientists worldwide in need of his laboratory’s expertise in studying different aspects of ribosome synthesis relevant to DBA. Not only is Steve the dedicated (and unpaid) DBAF Research Director, his laboratory provides valuable research support services to the wider DBA Community.

Date Funded 1/18:

Janis Abkowitz. M.D., from the University of Washington, Seattle, WA was awarded $63,120 to continue her project entitled, “The contribution of heme excess to macrocytic anemia in murine models of DBA.” They propose studying the relationships of heme synthesis, globin synthesis, ROS, P53 expression/activity, and ferroptosis (a recently described iron dependent, non-apoptotic death mechanism) in a new and more promising murine model of DBA, Rpl11 haploinsufficient mice, and in Rps19 deficient mice.

Date Funded: 12/17

The DBAF and DBA Canada proudly increased DBA awareness among attendees at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition held in Atlanta. The event was attended by over 20,000 worldwide hematologists, researchers and other health-related professionals. Visitors to the DBA booths received information regarding DBA clinical care, patient opportunities, and research.

Date Funded: 11/17

A DBAF grant of $20,000 was awarded to Dr. Anna Aspesi, a junior investigator who for the past 14 years has been working in various capacities (graduate student, postdoctoral fellow) in the laboratory of Dr. Irma Dianzani at the Universita del Piemonte Orientale in Novara Italy for the project entitled, “The problem of interpreting missense mutations of DBA genes: proposal of a new functional assay.” The aim of this study is using a functional complementation assay in order to determine if a variant of unknown significance is involved in the pathogenesis of DBA.

Date Funded: 11/17

The DBAF supported the 2017 GATA Meeting with a $3500 donation. The scientific program includes talks by more than 30 speakers who are international experts in the biology of GATA factors. The meeting will provide an excellent opportunity to discuss, amongst others, recent progress made through “omics” technologies in providing an unprecedented view of the transcriptional landscapes that GATA factors regulate and the mounting genetic and molecular evidence implicating GATA factors in human disease.

Date Funded: 7/17

DBAF and DBA Canada hosted a family meeting and donated $10,000 to Camp Sunshine.

Date Funded: 7/17

A DBAF grant of $56,021 was awarded to Vijay G. Sankaran, M.D., Ph.D., Harvard Medical School,  Broad Institute of MIT and Harvard, Boston Children’s Hospital, Boston, MA for the project, “Dissecting the genetic architecture of Diamond Blackfan anemia.” The goal of this proposal is to mine whole exome sequencing data to identify novel genes responsible for DBA. Offshoots of this study will be new approaches to identifying slice site mutations responsible for human disease and developing a database to study clonal hematopoiesis in DBA patients.  The latter will be important for understanding the progression of blood cancers in DBA patients.

Date Funded: 2/17

DBAF funded Barry H. Paw’s, M.D., Ph.D., Harvard Medical School, Brigham and Women’s Hospital, Boston Children’s Hospital, and Dana-Farber Cancer Institute, Boston, MA research project entitled, “Therapeutic targeting of protein translation in DBA” for $50,866. This application addresses the broad challenge of identifying new therapeutics for DBA patients. It involves the use of a new zebrafish model to monitor protein translation and has potential implications on gene discovery.

Date Funded: 12/16

The DBAF and DBA Canada proudly increased awareness among attendees at the 58th American Society of Hematology (ASH) Annual Meeting and Exposition held in San Diego. The event was attended by over 20,000 worldwide hematologists, researchers and other health-related professionals. Visitors to the DBA booths received information regarding DBA clinical care, patient opportunities, and research.

Date Funded: 8/16

Janis Abkowitz. M.D., from the University of Washington, Seattle, WA was awarded $60,238 for the project entitled, “The contribution of heme excess to macrocytic anemia in murine models of DBA.” They propose studying the relationships of heme synthesis, globin synthesis, ROS, P53 expression/activity, and ferroptosis (a recently described iron dependent, non-apoptotic death mechanism) in a new and more promising murine model of DBA, Rpl11 haploinsufficient mice, and in Rps19 deficient mice.

Date Funded: 7/16

DBAF has awarded Yigal Dror, M.D., The Hospital for Sick Children, Toronto, Canada, a $55,000 grant for the research project entitled, “Understanding the role of the FLVCR1 heme exporter and splicing regulators in the erythropoietic failure in Diamond Blackfan Anemia.” They hypothize that aberrant splicing of cellular transcripts that includes FLVCR1 aberrant splicing play an important role in DBA pathogenesis and that the erythropoietic defect in DBA HSCs can be rescued by expression of normal FLVCR1 or TRA2B cDNAs.

Date Funded: 6/16

A DBAF grant of $50,000 was awarded to John Strouboulis, Ph.D., Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology Hellas, Greece for his project, “Differential characterization of GATA1 and GATA1short protein interactomes in erythroid cells.” The project proposes to establish whether GATA1 has a direct regulatory role in RP gene expression in erythroid cells and, if so, how this may be affected by the GATA1s mutation.

Date Funded: 6/16

An award of $25,000 was given to Michal Hetman, M.D., Ph.D., of the University of Louisville, Kentucky for his project, “Identifying Small Molecule Compounds to Disrupt Ribosomal Stress Signaling.” This screen is distinct from other DBA drug screens in that this is a virtual screen where millions of chemical are virtually docked to the site of interaction between Rpl11 and MDM2. Chemicals identified in this virtual screen will be tested in various DBA models, including patient cells.

Date Funded: 3/16

The 14th Diamond Blackfan Anemia International Consensus Conference was held March 5-7 at the Ritz-Carlton Hotel in downtown Atlanta, Georgia. The overriding goal of this and past ICC meetings has been to identify therapies and strategies to improve the quality of life for patients and families with DBA.

Date Funded: 12/15

The DBAF and DBA Canada proudly increased awareness among attendees at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition held in Orlando, FL.

Date Funded: 12/15

The DBAF and DBA Canada provided a $56,225 grant to Colin Sieff’s, MB, BCh, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston Children’s Hospital, Boston, MA research project entitled, “Developmental erythropoiesis in a new murine model of Diamond Blackfan anemia.” The application describes a novel and potentially informative mouse model of DBA. The field has long awaited such a mouse as previous attempts to generate DBA mouse models have been disappointing in one way or another.

Date Funded: 4/15

The DBAF and DBA Canada awarded a grant to Johan Flygare, M.D., Ph.D. at Lund University in Sweden for his project entitled, “A novel group of kinase inhibitors for treatment of Diamond Blackfan Anemia.” Preliminary research has identified 12 potential drug targets compounds that rescue production of red blood cells in our RPS19-deficient mouse model for DBA. Dr. Flygare’s project will continue drug development using a completely novel strategy for treating DBA.

Date Funded: 2/15

The DBAF awarded a grant to Dr. Steve Ellis, Ph.D. at the University of Louisville to continue to provide experimental services to clinicians and scientists worldwide in need of his laboratory’s expertise in studying different aspects of ribosome synthesis relevant to DBA. Not only is Steve the dedicated (and unpaid) DBAF Research Director, he also writes the DBAF’s e-newsletter monthly Journal Club and his laboratory provides valuable research support services to the wider DBA Community.

Date Funded: 1/15

The DBAF, in collaboration with DBA-UK, awarded Nicholas James Watkins, Ph.D. at the University of Newcastle upon Tyne in the United Kingdom a grant for a project entitled, “Ribosome biogenesis, cellular signaling pathways and Diamond Blackfan anemia.” Dr. Watkins’ laboratory has recently identified two regulators of the 5S RNP signaling complex that could represent potential targets for the development of new drugs to treat DBA.

Date Funded: 1/15

The DBAF supported the 2015 Ribosome Synthesis Meeting held tri-annually with a donation. The meeting focuses on the mechanisms of ribosome assembly in eukaryotes and prokaryotes, the molecular basis for ribosomopathies, and the role of specialized ribosomes.

Date Funded: 9/14

The DBAF provided a grant for Dr. Shai Izraeli at Tel Aviv University for his project entitled, “A mouse model to study the role of GATA2 in anemia caused by GATA1s mutation.” If successful, this experiment will lead to a search for GATA2 “druggable” targets whose modification may at least partially ameliorate the anemia in DBA patients with GATA1s mutations.

Date Funded: 8/14

The DBAF, in partnership with DBA Canada, awarded a grant to Dr. David Bodine, Ph.D. at the National Human Genome Research Institute for his project, “Assay Development and Preliminary Screening of Small Molecules to Increase Ribosomal Protein Levels.” This project aims to screen thousands of potential drugs that may be able to increase the translation of ribosomal protein mRNA.

Date Funded: 8/14

DBAF and DBA Canada collaborated to continue funding Dr. Harvey Lodish’s project, “High-throughput screening identifies many novel potential therapies for Diamond Blackfan Anemia.” Without this grant, research would have halted at a critical juncture due to DoD reorganization and lack of funding. The Lodish group has identified a set of drugs that appear to work synergistically with steroids in stimulating erythropoiesis in mice.

Date Funded: 6/14

The DBAF awarded a grant to Vijay G. Sankaran, M.D., Ph.D. of Boston Children’s Hospital to fund a research project entitled, “Defining GATA1 Transcriptional Alterations in Diamond-Blackfan Anemia.” Dr. Sankaran was involved in the studies leading to the discovery of GATA1 as the first known non-ribosomal DBA gene and has since shown that ribosomal protein haploinsufficiency affects GATA1 expression. This award will allow for better understanding of the role of GATA1 in the altered red blood cell production observed in DBA, giving insight into what goes wrong in patients.

Date Funded: 5/14

A grant was awarded to Daniel Finley, Ph.D. at Harvard for his project entitled, “A new mode of ribosome regulation specific to reticulocytes.” The grant will allow the researchers to think about the problem of DBA in a new way as this project arose out of work on genetic mutant strains of mice with anemia that have exceptionally high ribosome levels (the opposite of DBA) due to a failure of ribosome elimination.

Date Funded: 4/14

The DBAF awarded a grant to Dr. Harvey Lodish at MIT for his project entitled, “High-throughput screening identifies many novel potential therapies for Diamond Blackfan Anemia.” This grant functioned as gap funding to maintain the progress of a project initially funded by the U S Department of Defense (DoD) in which over 2000 tested and FDA-approved therapeutic compounds were screened in hopes of obtaining “hits” that can stimulate red cell production in mouse models. Ten drugs were found to be successful stimulating red cell production in mice and then were rescreened in a new human cell culture system.

Date Funded: 3/14

The 13th Diamond Blackfan Anemia International Consensus Conference was held March 8-10 at the Ritz-Carlton Hotel in downtown Atlanta, Georgia. The overriding goal of this and past ICC meetings has been to identify therapies and strategies to improve the quality of life for patients and families with DBA.

Date Funded: 12/13

The DBAF and DBA Canada proudly increased awareness among attendees at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition held in New Orleans, LA from Dec. 7 – 10, 2013. The event was attended by over 20,000 worldwide hematologists, researchers and other health-related professionals. Visitors to the DBA booth received information regarding DBA clinical care, patient opportunities, and research.

Date Funded: 11/13

Dr. Johnson Liu at The Feinstein Institute for Medical Research was awarded a grant for the project, “Repairing Dominant Negative Mutation of RPS19 Gene by Spliceosome-Mediated RNA Trans-Splicing.” This approach takes advantage of the fact that human genes are made up of pieces of genetic information that are spliced together at the level of mRNA before they go on to create a protein.  The goal of this proposal is to swap one piece of coding information for another through a process called trans-splicing.  Using this approach, the coding information carrying a DBA-causing mutation will be swapped with normal coding information lacking the mutation. This project was co-sponsored with Diamond Blackfan Anemia Canada.

Date Funded: 10/13

Dr. George Thomas was awarded a grant for the research project entitled,The role of p53 in mediating the anemic response in DBA patients with defects in RPL5 or RPL11.” The long-term goal of this study is to understand the mechanisms through which red blood cell precursors in the marrow of DBA patients undergo programmed cell death rather than differentiate into mature red blood cells. The grant to the University of Cincinnati will provide support for Dr. Teng Teng on Dr. Thomas’ team. The team will investigate whether alternative pathways are at play in DBA patients with mutations in RPL5 and RPL11.  Overall, the goal of these studies is to define the molecular mechanisms by which defects in distinct ribosomal proteins affect the survival and maturation of hematopoietic cells, potentially leading to the development of more efficacious targeted therapies. This project was co-sponsored with Diamond Blackfan Anemia Canada.

Date Funded: 9/13

Dr. Steve Ellis’ research lab has been awarded a grant to continue important research support work at the University of Louisville, Kentucky. Dr. Ellis provides research support services to numerous worldwide DBA research groups. Dr. Ellis expects to broaden these activities over the next year as they continue to move forward with a gene discovery consortium, and develop these strategies as a tool for DBA diagnosis.

Date Funded: 7/13

Dr. Jingping Ge, Children’s Hospital in Philadelphia, was awarded a grant for her project entitled, “Role of TGF-beta signaling in the pathogenesis of DBA.” Dr. Ge’s preliminary data reveal that TGF-beta inhibits the reprogramming of differentiated cells to induced pluripotent stem cells (iPSCs) and even more so in DBA iPSCs. She hypothesizes that increased levels of TGF beta play an important role in causing the failure of erythropoiesis in DBA.  If so, then inhibiting the TGF beta pathway could be a therapeutic strategy in developing drugs to treat DBA. Dr. Ge is investigating the involved pathways by mRNA-sequencing and ribosome profiling. This research hopes to determine the role of TBF-beta signaling in DBA pathogenesis.

Date Funded: 7/13

Dr. John D Crispino, PhD., Northwestern University, was awarded a grant for the project, “Overriding GATA1 mutations in Diamond Blackfan Anemia.” The goals of this project are to: (1) characterize defects of mice that express GATA1s in place of full-length GATA1 and determine if overexpression of EKLF can rescue differentiation and (2) Identify small molecules that induce differentiation of GATA1s mutant erythroblasts. This project was funded with support from DBA Canada.

Date Funded: 6/12

Dr. Fredrick Goldman, University of Alabama at Birmingham, was awarded a grant for the project, “Toward a cure for DBA: creation of patient-specific gene corrected hematopoietic stem cells using induced pluripotent stem cell technology.” The goals of this research project are (1) to create an in vitro model of DBA using iPSC (induced pluripotent stem cell) for producing HSC (hematopoietic stem cells) by reprogramming patient cultured skin fibroblasts and (2) to use genetic recombination strategy to correct/replace the gene defect in iPS (induced pluripotent stem) cells derived from patients with the RPS-19 mutation. In general, this research may set the stage for an important patient-specific model system for studying developmental and physiological aspects of DBA that are currently unavailable.

Date Funded: 6/12

Dr. Steve Ellis’ research lab has been awarded a grant to continue important research support work at the University of Louisville, Kentucky. Dr. Ellis provides research support services to numerous worldwide DBA research groups. Dr. Ellis expects to broaden these activities over the next year as they continue to move forward with a gene discovery consortium, and develop these strategies as a tool for DBA diagnosis.

Date Funded: 6/12

The DBAF co-sponsored the 9th International Conference on Ribosome Synthesis. This meeting brings together investigators from all over the world to focus on issues related to ribosome synthesis.

Date Funded: 2/12

The DBAF supported the Twelfth Annual Diamond Blackfan Anemia International Consensus Conference sponsored by the Daniella Maria Arturi Foundation.

Date Funded: 11/11

Dr. Adrianna Vlachos was awarded a grant for the project “A Strategic Approach to Gene Discovery in Diamond Blackfan Anemia”. Diamond Blackfan anemia (DBA) is the first known “ribosomopathy”. There are two objectives for this study. The first objective is to perform whole genome Single Nucleotide Polymorphism Array (SNP-Array) Genotyping on DBA patients who have not had mutations detected by sequencing. The second objective is to perform a pilot study of whole exome sequencing on DBA patients who have not had mutations detected by SNP-Array or the sequencing projects.

Date Funded: 8/11

Dr. Hanna Gazda was awarded a grant to continue her efforts for the project “New gene discoveries and biology of ribosomes in Diamond Blackfan Anemia.”. The aim of this study is (1) to perform comparative genomic hybridization to search for deletions and duplications in ribosomal protein genes that could not have been picked up by DNA sequencing; (2) to perform whole exome sequencing (“next generation” sequencing) to potentially identify non-ribosomal protein genes that may be mutated in DBA.

Date Funded: 8/11

Dr. Irma Dianzani was awarded a grant to for the project “Understanding the causes of remission in DBA patients”. The goal of this project is to understand the molecular basis of remission in DBA patients. Dr. Dianzani proposes to identify genes that, when mutated, lead to remission in DBA patients.

Date Funded: 7/11

Dr. Johan Flygare was awarded a grant to for the project “Identification of Genetic and Chemical Modifiers of Erythropoiesis in Diamond Blackfan Anemia”. The project goal is to develop better treatments for DBA by identifying chemical compounds and molecular pathways that promote proliferation of RPS19-deficient erythroid progenitor cells.

Date Funded: 10/10

Emanuela Tolosano, Ph.D., Professor at the University of Torino School of Medicine, was awarded a grant to fund a project aimed at defining the role of the Feline Leukemia Virus, subgroup C, Receptor (FLVCR) in the pathogenesis of Diamond-Blackfan anemia. FLVCR encodes a protein that exports excess heme from cells. It has been suggested that defects in globin synthesis, perhaps as a result of ribosomal protein mutations, could result in excess heme in erythroid progenitors that would need to be exported from cells to reduce heme toxicity. Thus, FLVCR could play an important role in DBA pathogenesis.

Date Funded: 7/10

Hanna T. Gazda, M.D. Instructor in Pediatrics Harvard Medical School was awarded a grant to continue her efforts to identify genes mutated in patients with DBA. The aim of this study is (1) to perform comparative genomic hybridization to search for deletions and duplications in ribosomal protein genes that could not have been picked up by DNA sequencing; (2) to perform whole exome sequencing (“next generation” sequencing) to potentially identify non-ribosomal protein genes that may be mutated in DBA. This project will result in a more complete picture of the genetic causes of DBA and the pathogenic mechanisms that result.

Date Funded: 5/10

Paul de Figuieredo, Ph.D., Assistant Professor, Texas A&M University was awarded a grant for the project “Discovering therapeutics for DBA”. The long-term goal of this study is to develop small molecule therapeutics for Diamond Blackfan Anemia (DBA), by screening for molecules that overcome growth defects associated with decreased expression of ribosomal protein S19 in a yeast model of DBA.

Date Funded: 2/10

The DBAF supported the Eleventh Annual Diamond Blackfan Anemia International Consensus Conference sponsored and organized by the Daniella Maria Arturi Foundation.