Hematopoiesis—the development and differentiation of stem cells into multiple types of blood cells—occurs throughout life, and its dysfunction is associated with low blood counts or leukemia. Dr. Dunbar’s research focuses on understanding the process of hematopoiesis in vivo, as well as on optimizing and improving the safety of gene transfer into primary hematopoietic cells for therapeutic purposes. Her goals are synergistic: insight into the control of hematopoiesis is required to successfully manipulate and genetically modify hematopoietic cells; conversely, genetic marking of hematopoietic stem and progenitor cells has provided novel insights into lineage relationships, stem cell dynamics, and stem cell numbers in vivo that are applicable to gene therapy, stem cell transplantation, and other clinical interventions.
For over twenty-five years, Dr. Dunbar’s laboratory has had the privilege of utilizing a rhesus macaque transplantation model. Her facility is one of only a handful worldwide able to successfully support non-human primates through stem cell transplantation. This model provides unique and highly relevant insights into hematopoiesis and has resulted in successful optimization of gene and cell therapy approaches later translated successfully into human clinical trials. Her studies also encompass informative in vitro, murine, and human xenograft models.
Dr. Dunbar and her colleagues have mapped the number, frequency, and output of individual stem and progenitor cells over time in the rhesus macaque model, via a quantitative, informative and high-throughput genetic barcoding approach. Novel and biologically/clinical relevant findings regarding clonal stability, frequency, lifespan, geographic location, and lineage bias have been generated utilizing this approach. The approach has offered direct evidence for peripheral expansion and long-term persistence of natural killer cell clones, beginning to elucidate a mechanism for NK cell memory.
In addition, Dr. Dunbar’s team has developed a number of new gene therapy vector systems for high efficiency transduction of monkey and human hematopoietic stem and progenitor cells. The growing evidence that integrating gene therapy vectors can activate adjacent proto-oncogenes, both from human clinical trials and from primate studies in Dr. Dunbar’s laboratory, has spurred intense investigation into the process of vector integration into the genome. Dr. Dunbar has been a leader in this research for the past fifteen years. Her laboratory continues to optimize vector and transduction approaches that can retain the therapeutic potential of stem cell gene therapies while avoiding genotoxic events. Most recently, her laboratory has focused on developing, testing and optimizing gene-editing technologies such as CRISPR/Cas9 to engineer hematopoietic stem and progenitor cells and create relevant disease models in rhesus macaques.
Dr. Dunbar’s laboratory has also developed induced pluripotent stem cells (iPSC) in the rhesus model, and is investigating whether their use in regenerative medicine approaches can be made safe and effective. Her group developed the first non-human primate autologous teratoma model, and demonstrated functional bone regeneration in vivo from rhesus macaque iPSC. Active research directions include testing of in vivo cardiac and hepatic regeneration from rhesus macaque iPSC.
Dr. Dunbar’s recent clinical work has focused on strategies to expand human hematopoietic stem cells in vivo, most notably in a trial of the stem cell stimulatory cytokine analog eltrombopag for the treatment of patients with severe refractory aplastic anemia. This trial resulted in the first FDA approval for new drug to treat aplastic anemia in over 30 years. Her group has also used human iPSC to model bone marrow failure disorders, including GATA2 deficiency and telomeropathies, in order to gain insights into pathophysiology and investigate new treatment approaches.
Cynthia Dunbar CV (PDF, 409KB)