Barbara Alving, MD Director, National Center for Research Resources 6701 Democracy Boulevard MSC 4874 Bethesda, MD

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1 Barbara Alving, MD Director, National Center for Research Resources 6701 Democracy Boulevard MSC 4874 Bethesda, MD Via Dear Dr. Alving: The American Society of Hematology (ASH) appreciates the opportunity to provide comments on the National Center for Research Resources (NCRR) efforts to update its Strategic Plan. ASH represents approximately 14,000 clinicians and scientists committed to the study and treatment of blood and blood-related diseases. These diseases encompass malignant hematologic disorders such as leukemia and lymphoma, non-malignant conditions including anemia and hemophilia, and congenital disorders such as sickle cell anemia and thalassemia. Our members are active participants in NIH s programs, recipients of NIH grants, and contributors to NIH s research accomplishments. Hematology researchers have been pioneers in new fields of biomedical investigation and have translated new scientific discoveries into improved diagnostic, therapeutic, and preventive strategies. Hematologists have been pioneers in the fields of bone marrow transplantation, gene therapy, and many drugs for the prevention and treatment of heart attacks and strokes. Hematology research has been a pathway for new avenues of inquiry and has actually spawned entire new disciplines. ASH would like to address a number of the specific areas where NCRR is seeking input during its strategic planning process. What are the most significant trends, developments and/or needs in biomedical research that are likely to materialize over the next five years, and what can NCCR do to be prepared to respond to them? ASH has undertaken a comprehensive strategic planning process to identify and prioritize the most fertile areas of current research in hematology and calls NCRR s attention to the ASH Agenda for Hematology Research. In this document ASH identifies the major scientific priorities for future hematology research.

2 Page 2 Stem Cells Stem cells (embryonic and adult ) offer tremendous therapeutic promise for a large number of degenerative disorders of wide socio-economic and health impact. ASH encourages NCRR to provide infrastructure support of this emerging field in terms of: 1. Supporting animal models (e.g. zebrafish and mouse) that will allow investigators to exploit molecular and mechanistic research tools to define key issues related to: the pathways of lineage specification, differentiation, and self-renewal; the role of the stem cell microenvironment in determining stem cell plasticity; and defining biology of how aging effects stem cell behavior. 2. Supporting human subjects research through CTSA and other mechanisms to define the best practices for stem cell therapy and to understand mechanistic issues related to stem cell therapy, such as the immunomodulatory effects of stem cell therapy. 3. Supporting embryonic stem cell research by fostering development and distribution of human ES cell lines. Genetics and Genotype-Phenotype Associations Advances in DNA sequencing strategies and in rapid, large scale assessment of genetic variability in populations (genome wide association studies) hold great promise to unlock the mysteries of numerous complex disorders having heritable components. This heralds a true new era of personalized medicine with potential to predict disease risk, design novel prevention strategies, and develop new therapeutic interventions based on unexpected discoveries of cellular and genetic pathways involved in disease pathogenesis. Success in these endeavors will require the ability to recruit large sets of human subjects, and to assemble banks of human tissues, DNA, and RNA. Most importantly, human subjects information needs to be stored in such a manner that is electronically accessible, de-identified, and categorized in a manner that is reproducible and meaningful across institutions. NCRR can lead the way in establishing national standards for biobanking and for uniform phenotyping of human subjects. Furthermore, with NCRR support, mechanisms to link phenotypic data to the electronic medical record can be developed so that research subjects can be shared across institutions, vastly increasing the power of these studies. Genomics/Proteomics The ability to characterize normal and disease tissues and cells with respect to gene expression and function (transcriptomes, epigenomes, etc.) is improving rapidly and ASH encourages NCRR to continue support of these essential technologies. Similar to the advances in genetics/genomics technology described above, recent advances in mass spectrometry and bioinformatics will lead to large scale proteomic analysis of human tissues associated with disease and disease risk. The ability to describe phospho-proteomes and to perform comparative proteomics on cells and tissues (such as leukemic bone marrow) will further push us towards personalized medicine and increase the potential to predict disease risk, design novel prevention strategies, and develop new therapeutic interventions based on unexpected discoveries of cellular and genetic pathways involved in disease pathogenesis. ASH encourages NCRR to support continued development of these technologies. Issues related to phenotyping and biobanking are equally relevant to proteomics as genomics. Targeted Therapeutics Progress in clinical gene transfer has helped to define the safety profiles of viral and non-viral gene delivery vehicles, particularly AAV and antiviral vectors which are emerging as vectors of

3 Page 3 choice for genetic disease. Proposed projects in the functional genomics of cancer, especially the hematologic malignancies, will provide further valuable information and should be strongly supported. Moreover, the development of molecular probes to better understand biological pathways is likely to lead to the identification of effective small chemical and peptidyl therapeutic molecules, building on examples such as the successful treatment of chronic myeloid leukemia with imatinib. The emerging field of small regulatory RNAs and inhibitory RNAs will create novel possibilities for clinical intervention. There are several priority areas for future progress relevant to hematology, including: (1) targeting neoplastic stem cells; (2) regenerative medicine; and (3) cell and gene therapy. ASH encourages NCRR to foster development of research tools with broad applicability in these areas, including RNAi libraries in suitable targetable vectors, chemical libraries, gene transfer vectors, etc. Furthermore, efforts to maintain accurate, accessible databases linked to chemical libraries and RNAi libraries are encouraged. Blood and Blood Disorders As noted earlier, ASH has recently drafted the ASH Agenda for Hematology Research that addresses many of the questions raised by NCRR with a focus primarily on research related to blood and blood diseases. A summary of the highest priority research areas identified in this agenda and their relationship to NCRR follows: 1. Normal and Pathological Hematopoiesis Hematopoiesis is a paradigm for the development of other tissues and organs from undifferentiated progenitor cells, and, therefore, knowledge about molecular mechanisms of hematopoiesis has broad practical implications. Much of our current knowledge of hematopoiesis comes from study of rare human disorders (some of which is supported by NCRR through their Rare Diseases Network) and through studies of animal model systems, particularly mouse and zebrafish. ASH encourages NCRR to continue and expand support of these vital programs. One of the highest priorities for continuing success in translating biological sciences into clinical medicine is advancing the study of normal and abnormal hematopoiesis. There are several priority areas for future progress that will benefit from continued NCRR infrastructure support, including: pathogenesis of the anemia of chronic inflammation (ACI); actions of hematopoietic growth factors on non-hematopoietic tissues; therapeutic potential of hematopoietic cytokines; regulation of hematopoiesis; molecular profiling of hematologic malignancies; neoplastic stem cells; immune therapies for hematologic malignancies; and treatment of hematologic malignancies. 2. Immunobiology Hematopoietic stem cells give rise to all cellular elements of both the innate and adaptive immune system. Many of these cells circulate in the blood and lymphatic systems throughout life, and this provides the primary mechanism whereby immune responses are efficiently directed to local sites of infection and inflammation. Hematology research has contributed substantively to remarkable advances in our understanding of the mechanisms of innate and adaptive immune recognition, response, and regulation in the past 20 years. These basic advances in immunobiology have already led to the development of many new therapies for a variety of autoimmune and inflammatory diseases as well as cancer. Immune cytokines, monoclonal antibodies, and agents that target specific receptors or adhesion pathways on immune cells are just a few examples of these new therapeutics. Further research in this area will undoubtedly lead to new approaches to improve outcome of hematopoietic stem cell transplantation, facilitate

4 Page 4 solid organ transplantation, control autoimmune diseases, induce effective tumor immunity, design more effective vaccines, and limit tissue damage due to inflammation. There are several priority areas for future progress, including: immune recognition; mechanisms of immune response; normal and abnormal mechanisms of immune regulation; transplantation immunology; immune therapy; innate immunity; lymphopoiesis; and immune cell trafficking. 3. Thrombosis and Vascular Biology In the U.S. there are about 500,000 venous thromboembolic events, 1.1 million myocardial infarctions, and more than 150,000 stroke deaths annually. Atherothrombosis is the primary cause, and, therefore, the mechanisms involving both thrombosis and atherosclerosis are central to the pathogenesis of a disease that is the dominant cause of morbidity and mortality in the Western world. Platelets, thrombin generation, and fibrin formation are critical components of arterial thrombosis and atherogenesis, and thrombosis is the major mechanism leading to the acute events of atherosclerosis. There are several priority areas for future progress that will benefit from NCRR infrastructure support via CTSA and other mechanisms, including: antithrombotic therapy; early mechanisms of arterial and venous thrombosis; genomics, transcriptomics, and proteomics; cancer-related thrombosis; thrombosis and vascular disease unique to specific populations (e.g. women and the elderly); and stroke. From the standpoint of achieving the broadest impact among investigators, what new or expanded research resources and/or animal models should be developed over the next five to eight years? The ASH Agenda for Hematology Research also identifies the Society s highest priorities for research infrastructure in the areas of training and institutional and national core resources. In response to NCRR s request for specific information on the need for new or expanded research resources and/or animal models, ASH would like to first address the need for research resources and/or animal models pertaining to the individual research areas identified in the Society s response above to NCRR s initial strategic planning question, followed by a description of the need for national resource centers and training. Specific Research Area Needs There is a specific need for research resources and/or animal models pertaining to the individual research areas the Society has identified above. 1. Hematopoietic stem cells A. Advanced imaging technologies are needed to track stem cells after infusion. Increased emphasis in this area is needed in the immediate future to bolster our understanding of stem cell homing, trafficking, and vital steps in the engraftment process. B. Improved methods for expansion of stem and progenitor cell populations are necessary for their mobilization into the blood and enhancement of engraftment potential of stem cells. C. Availability of stem cells for clinical transplantation, including cord blood stem cells and adult stem cells from minority populations, should be expanded, as this will facilitate the application of stem cell therapies in underserved populations. Cord blood banking must also be expanded.

5 Page 5 D. Expanded numbers of uncontaminated ES cell lines should be developed and provided to the scientific community. Providing such cell lines will permit critical studies be undertaken to compare the regenerative capacity of ES cells compared with adult stem cells in an attempt to develop new treatments for many debilitating and fatal diseases. 2. Normal and Pathological Hematopoiesis A. Development of Micro (mi)rna technologies. B. Continued support of Rare Diseases Networks. C. Support for proteomics, genomics, and cell targeting methodologies. D. Support for biobanks and human phenotyping resources. 3. Hematologic Malignancies Future research in hematologic malignancies should be directed at molecular profiling and curating of tumor cells aided by high density genomic arrays, as well as epigenome, proteome, and phospho-proteome analyses. This effort should result in a more comprehensive assessment of the deregulated molecular pathways and potentially druggable targets in hematologic malignancies. 4. Targeted and Gene Therapies To help achieve the goal of bringing novel targeted agents to treat hematologic disorders to the clinic more quickly, resources must be deployed for the concerted promotion of studies in: A. Target identification and validation. B. Virtual and physical screening for lead compounds. C. Pre-clinical investigations, including the design of the most appropriate animal models, medicinal chemistry, pharmacokinetics, and toxicology. D. Gene transfer, where the most urgent needs are resources for pharmacology/toxicology testing and for production of clinical grade vectors. E. Development of multidisciplinary teams with clinical and basic science expertise in stem cell biology, cell transplantation methodology, clinical trials design, ethics, and organ-specific knowledge. 5. Thrombosis and Vascular Biology New animal models are desperately needed in these areas. There are a number of existing models for arterial thrombosis, but each likely measures different aspects of physiology (for example, some expose subendothelium and some do not). These models are cumbersome and expensive and not amenable to high throughput or genetic analysis. No good models of venous thrombosis exist. Adequate animal models are needed to define the pathogenesis of both venous and arterial thrombotic disorders, and to determine gender and age related influences. The development of such models and the generation of genetically altered animals that more closely mimic the human disease processes will allow for molecular and cellular analysis of the causes of atherothrombosis and evaluation of the efficacy of novel drugs against unique targets. Lack of appropriate animal models has limited progress in studying the basic hemostatic mechanisms in the cerebrovascular circulation, including the role of platelets, coagulation, and fibrinolysis in the pathogenesis of stroke.

6 Page 6 National Resource Centers National resource centers that support efforts related to blood diseases would have significant impact on research in these disorders. Given advances in information storage and technology, these may be virtual centers rather than localized or centralized institutional centers. These collaborative networks of multiple academic medical centers would: (1) establish centralized disease-based registries and databases for both common and rare disorders; (2) collaborate to design and prioritize clinical trials; (3) collect and store biological specimens for future researchers; and (4) coordinate at the national level the prospective recruitment and registration of patients with specific disorders into available clinical trials. Particular examples of such national resource centers would include networks for rare hematologic disorders and hematologic malignancies. For rare blood disorders, the national resource centers would provide detailed phenotyping. The maintenance of detailed databases and easy access to these databases would facilitate clinical studies of patient populations whose prevalence is too low to allow individual clinical trials. For example, thrombotic thrombocytopenic purpura (TTP) is a disorder whose etiology has recently been identified. The development of diagnostic and treatment strategies requires access to numerous patients to support clinical trials, but a disorder like TTP requires pooling of patient data, since no one center sees sufficient numbers of these patients. Large patient populations could be characterized over decades, as hematology equivalents to the Framingham study model. Patient data and materials would be deposited, and investigators would have access to this data to explore new hypotheses. This data could provide phenotyping for long-term epidemiologic outcome studies, which are critical to define the role of genetic variation in the development and progression of disease, and are not typically funded in investigator-initiated grant proposals. These national resources may also collaborate with the National Marrow Donor Program and a national cord blood facility to supply well-characterized stem cells to support individual research projects. The creation and activities of multi-institutional, translational research consortia focused on specific disorders (e.g. hematologic malignancies) would help create banks of tissue samples, which could potentially be linked to accessible clinical profiles and outcomes. The consortia would also perform molecular profiling and curating of the tumor cells aided by highdensity genomic arrays, as well as epigenome, proteome, and phosphoproteome analysis. This effort should result in a more comprehensive assessment of the deregulated molecular pathways and potentially druggable targets in hematologic malignancies. National centers could also be a resource for the development of animal models that are not currently available to study disease pathogenesis. Examples are the absence of adequate animal models to study the pathogenesis of thrombotic disorders, such as venous thromboembolism, atherosclerotic plaque development, stroke, or the role of platelets in angiogenesis and the absence of a mouse model for atherothrombosis. Given the importance of animal models in the study of vascular biology, these genetically modified animals would be available to the research community. Furthermore, multidisciplinary efforts to develop novel technology for exploiting these animal models could be shared with the general research community or made available in regional or centralized facilities. The recently-introduced CTSA (Clinical Translational Science Award) Program seeks to transform the local, regional and national environment for clinical and translational science, thereby increasing the efficiency and speed of clinical and translational research. What considerations will be most crucial to the long-term success of this initiative?

7 Page 7 The future of hematology requires that research in diverse areas of basic science be integrated and translated into novel, decisive therapies that will effectively prevent or cure serious blood and vascular diseases. Integrated, multidisciplinary institutional research centers can provide invaluable synergies at many stages in the translational arc, from efficiently stimulating the most important basic research within individual investigators laboratories, to encouraging active collaboration between multiple investigators around common themes, to supporting novel clinical trials. ASH therefore considers it a high priority to ensure that the CTSA program creates such integrated, multidisciplinary institutional research centers that foster accelerated progress from discovery to prevention and cure of hematologic disorders by supporting: 1. Basic research cores, supporting sophisticated technical capabilities not easily duplicated within individual laboratories but in high demand. These might include stem cell production, in vivo xenogeneic transplant assays, bioinformatics, in vivo bioimaging, in vitro vascular modeling and vascular dynamics, and tissue engineering and nanotechnology. 2. Translational and clinical research cores, including genomics and proteomics cores, small molecule discovery facilities, pharmacokinetic and pharmacodynamics units, clinical trial support and monitoring units, biostatistical cores, and high quality phenotyping cores. For early-stage clinical trials in humans, core facilities must be able to provide clinical grade reagents and regulatory support and facilitate the combined use of therapeutic agents from different sources. 3. Seed funds for novel research, including pilot project awards, collaborative research proposals bridging multiple investigators from diverse scientific disciplines, and translational research proposals testing new reagents in proof-of-concept clinical trials. 4. Prevention/outreach education materials. 5. Education and training in clinical and translational research methodologies. 6. Career development support for physician and PhD investigators involved in clinical and translational research. Programs should support trainees at all levels, including undergraduate, pre-doctoral, postdoctoral, early faculty career, and mid-career transition. Despite significant progress, research institutions serving predominantly minority and underserved populations face stiff challenges. What can NCRR do to most effectively support the long-term advancement of these institutions? The long term fiscal and research health of institutions serving predominantly minority and underserved populations is of absolute critical importance to ASH. Certain hematologic disorders such as sickle cell disease predominantly effect minority communities and minorities are often under-represented in clinical research of the common hematologic disorders such as leukemia, lymphoma, and thrombosis. Furthermore, availability of stem cells for clinical transplantation, including cord blood stem cells and adult stem cells from minority populations, is currently limited and must be expanded, as this will facilitate the application of stem cell therapies in underserved populations. Research institutions serving predominantly minority and underserved populations are poised to deliver high quality care and to help solve these important problems, but cannot succeed under the constraints of current financial models. NCRR can foster the health of underserved and minority populations by fostering the financial health and research robustness of institutions that serve them. This can be accomplished by supporting graduate and postgraduate training, faculty career development, capital needs, and research infrastructure at these institutions. Providing support to these institutions so that they can import best practices for clinical research that emerge from the CTSA program should be considered.

8 Page 8 NCRR has, and will continue to, work closely with many federal and private sector institutions, agencies, and organizations. Looking forward, what organizations should NCRR seek out for future partnerships to most effectively support, expand, and advance its programs and services? ASH encourages NCRR to continue to work closely with the leading medical and scientific societies, including ASH, as these societies maintain strong communication programs with their members and act as an interface between their membership and NIH. Among the federal agencies that are critical to the mission of ASH are FDA, CDC, and the other Institutes/Centers within NIH (especially NHLBI, NCI, NIDDK, and NIA); NCRR should continue to collaborate with these federal agencies to advance its mission. Of particular concern to ASH is the relationship of the CTSA program to NCI-sponsored Cancer Centers. It is crucial that the CTSA and Cancer Center programs work together so that local institutional resources are not diluted and synergies can emerge. Collaboration with successful CDC programs in hemostasis and thrombosis is likewise encouraged to foster clinical and translational research. ASH also encourages NCRR to collaborate with those organizations involved in setting standards for and certifying clinical training in medical specialties (e.g. RRC, ACGME, specialty/subspecialty Boards, and clinical training program directors) so that the goals and plans developed for research training ( T and K programs) are aligned with needs for Board certification for physician scientists. ASH commends NCRR on its willingness to involve the Society and the biomedical research community in the development of its updated Strategic Plan. The Society looks forward to continuing to work with the Center on issues addressing the needs of hematologic researchers. If you have questions or need additional information, please contact ASH Research Advocacy Manager Tracy Becker at tbecker@hematology.org or Sincerely, Andrew I. Schafer, MD President