New Therapies for Sickle Cell Anemia in the Genome Era

Summary of Meeting Conclusions

(Summary order does not convey priority)

  1. The time is propitious to bring to bear the developing tools and approaches of genomics to develop markedly more effective therapies for sickle cell disease. The NIH should play a lead - but not exclusive - role in developing and supporting such applications of genomics to sickle cell disease. For this effort to succeed, both the community of existing sickle cell disease researchers and the genomics community must be actively involved and integrated with each other to a degree that they have not been previously. Importantly, the community of individuals, families, and population groups affected by sickle cell disease must also be actively involved. As sickle cell disease is a global health issue, with over 95% of affected individuals living outside the United States, the application of genomics to sickle cell disease requires a global perspective and involvement as well. Within the NIH, a number of institutes and centers should be involved in cooperative design and support of new initiatives in this area.
  2. An innovative multidisciplinary Sickle Cell Disease Research Network with a central prospective registry of well phenotyped patients should be established. Features of such a network might include:
    • Inclusion of environmental, social, cultural, genetic data
    • Quality of life data
    • Careful attention to human subjects issues, well consented with recontact possible
    • Repositories of DNA, cell lines, mRNA, and plasma (the latter two from individuals when both symptomatic and asymptomatic)
    • Standardized phenotypes
    • Open access to materials and data
    • Longitudinal follow-up
    • Clinical trials database
    • Collaborative community partnerships, both in design and implementation
    • A newborn cohort
  3. There are many promising ways to apply genomics tools and approaches to sickle cell disease. Given the phenotypic diversity of sickle cell disease, identification of genetic modifiers is a particularly promising approach. Methods to this might include case/control studies and/or studies of twins, of sib pairs and of individuals with unusually mild phenotypes. International collaboration might be particularly helpful here. With the anticipated release in 2004 of a draft haplotype map, the possibility of haplotyping scores of patients with sickle cell disease to look for genetic modifiers and other clues to disease pathophysiology is an exciting avenue of research. A search for genetic modifiers in applicable transgenic animal models might also prove beneficial.
  4. Another genomic opportunity is performing proteomic and mRNA microarray-based analyses of bone marrow (if available), leukocytes, erythrocytes and their precursors, endothelial cells, etc. from a variety of patients with differing disease involvement.
  5. Genomics could also be brought to bear fruitfully through chemical genomics. Small molecule screens should be utilized to investigate possible new targets for therapeutics for sickle cell disease. Target-based compound screens to explore such possibilities as hemoglobin F induction, nitric oxide, antithrombotics/anticoagulants and other agents that might affect adhesion, inflammation, or oxidation would also be useful.
  6. Bringing new people and disciplines into the field is crucial. It is important to increase the number of basic, clinical, and social science researchers doing research on sickle cell disease. There are a number of ways to do this. Perhaps the most important is to renew a sense of excitement and promise in sickle cell disease research, so that it attracts young and/or new researchers to the field. Integrating genomics, proteomics, and high-throughput screening expertise into sickle cell research will help accomplish this. Appropriate support for training and retention of researchers, especially young ones, focused on sickle cell disease will also be important.
  7. All new research should be informed by the historical, social, economic, and cultural context of research and health care in sickle cell disease. This becomes increasingly important as research becomes increasingly applicable to health outcomes.
  8. There is need for a wider availability of clinicians able to care expertly for individuals with sickle cell disease. There is also need for therapies that are demonstrated to be effective, such as hydroxyurea, to be made more widely available to those with the disease. Further promulgation of a standardized care model should be pursued. Community and public education programs might also prove helpful. While the NIH should be involved in addressing these needs, it is beyond the mandate and the resources of the NIH alone to do so optimally, so other agencies, such as the Health Resources and Service Administration (HRSA), the Centers for Disease Control and Prevention (CDC), and the Agency for Healthcare Research and Quality (AHRQ) must also be involved.
  9. Core resources of biological materials, including such materials as transgenic mice for drug screening, a DNA construct repository, antibodies to sort erythroid progenitors, cord blood banks for SCD and thalassemia cells, and relevant stem cells should be made available to researchers.
  10. Core resources for drug development, e.g., toxicology, non-human primates, and infrastructure for Phase I and II trials should also be made available. The new NIH Roadmap goals for translational research should be highly relevant here.
  11. There is the need to develop new models to study hemoglobin F reactivation, especially in adult cells, such as human cell lines that respond to switching agents.
  12. New and better gene transfer vectors that are safe and efficient, including non-integrating systems, targeted integration, and homologous recombination should be developed.
  13. The NIH should take the lead in establishing a working group in 2004 to define SCD severity by strict standardized criteria.

Last updated: November 22, 2013