KL2 Scholar Studies Novel Hematopoietic Stem Cell Approach to Sickle Cell Disease Treatment

Elizabeth Stenger, MD, MSc, assistant professor, Department of Pediatrics, Emory University School of Medicine, received a K23 award for her work on improving haploidentical hematopoietic stem cell transplantation in sickle cell disease using autologous mesenchymal stromal cells.

Sickle cell disease is a group of inherited red blood cell disorders characterized by abnormal hemoglobin (hemoglobin S). Normally these cells are disc-shaped, giving it the flexibility to easily move throughout the body to deliver oxygen. Sickle hemoglobin, however, forms hard rods within the cell, changing it into a more sickle-shape. These cells are stiff, sticky, and inflexible, latching onto the blood vessel walls during transport and causing blockages that slow or stop the flow of oxygen to nearby tissues, causing severe pain, organ damage, and stroke.

Lack of tissue oxygen can cause attacks of sudden, severe pain called pain crises. These pain attacks can occur without warning, and a person often needs to go to the hospital for effective treatment. Oxygen depletion can also lead to organ damage. Since the cells cannot change shape easily, they tend to burst apart or hemolyze. While normal red blood cells will live 90-120 days, sickle cells die around day 10 to 20.

The body is designed to create blood cells to replace the old, but it struggles to replace sickle cells at the rate they are destroyed. This leads to lower red blood cells than normal. Sickle cell disease is a life-long illness, and while its severity differs from person to person, the average life expectancy of a patient in the United States is decreased significantly at 40-60 years. Sickle cell disease affects approximately 100,000 Americans and millions worldwide.

Despite medical advances like hydroxyurea medication and chronic transfusion, these individuals have significant morbidity and early mortality. Hematapoietic stem cells are the only stem cells that will reconstitute the hematapoetic system or bone marrow. Hematapoietic stem cell transplantation (HSCT) is the only readily available and proven curative therapy for sickle cell disease. While gene therapy will likely prove to be curative for SCD, it is still being evaluated on small, ongoing clinical trials. The healthy hematopoietic stem cells, which can be derived from a healthy donor’s bone barrow or peripheral blood, or umbilical cord blood, are transfused via IV.

Unfortunately, the majority of individuals with SCD do not have a suitable genetic match within either their family (matched related donor) or the National Marrow Donor Program (unrelated donor). While outcomes has been very successful following a matched-related donor transplant, differences between the recipient and donor immune systems following unrelated or mismatched-related (haploidentical) transplant remain a significant hurdle. This includes graft-versus-host disease, in which donor immune cells attack the recipient’s organs/tissues, and rejection, in which recipient immune cells attack the donor hematopoietic stem cells. Using a haploidentical donor, up to 40% of SCD patients reject the donor cells, leading to a significant unmet clinical need.

Stenger specializes in hematopoietic stem cell transplant for non-malignant blood disorders, those like acquired or congenital bone marrow failure and sickle cell disease, that affect the production and function of blood cells, and whose beginnings emerge in the blood marrow. She aims to decrease the immune-mediated complications of hematopoietic stem cell transplant, including through the use of cellular therapy. Specifically, she was interested in mesenchymal stromal cells, which have the ability to regulate the immune system, which gives them unique potential to overcome the engraftment barrier following haploidentical transplant for sickle cell disease. Mesenchymal stromal cells can be expanded outside the body from a small sample of bone marrow and can differentiate into bone, cartilage, fat, and muscle. These cells have the potential to support donor hematopoiesis, the proliferation of new blood cells in the body, and to inhibit the residual recipient immune system that drive rejection. In preclinical studies, these cells have demonstrated promotion of hematopoietic stem cell engraftment, establishing its possible efficacy. While these cells can be obtained from any donor (recipient, hematopoietic stem cell donor, or another person), she believes recipient-derived (autologous) cells are less likely to undergo destruction in the body and thus may be more potent.

Stenger was part of ACTSI’s KL2 Mentored Clinical and Translational Research Scholars Program, graduating with her Master of Science in Clinical Research last May. She is also the co-principal investigator for a pilot study of Abatacept (CTLA4 blockade) to prevent graft vs host disease in pediatric patients undergoing hematopoietic stem cell transplantation for non-malignant blood disorders, and the site principal investigator for the Primary Immune Deficiency Treatment Consortium, a U54-sponsored program investigating the outcomes for patients undergoing HSCT for primary immune deficiencies. “The years of support from the KL2 program for my research and career development have been critical towards my longterm goal to become an independently funded clinician-scientist,” said Stenger.

The goal of the KL2 program is to support career development for junior faculty (MD, PhD, or MD/PhD) from a wide variety of disciplines at Emory University, Morehouse School of Medicine (MSM), University of Georgia College of Pharmacy, and Georgia Institute of Technology (Georgia Tech) to become independent, established, and ethical clinical and/or translational research investigators. The Emory Master of Science in Clinical Research (MSCR) degree program, from the Laney Graduate School at Emory, provides didactic and mentored clinical and translational research training. The degree is designed for participants who hold a doctorate or equivalent degree (such as physicians and PhD-level scientists) or predoctoral trainees enrolled in a dual degree program (MD/MSCR and PhD/MSCR tracks) and have demonstrated a commitment to a career in clinical investigation.

The ACTSI is a city-wide partnership between Emory, MSM, and Georgia Tech and is one of a national consortium striving to improve the way biomedical research is conducted across the country. The consortium, funded through the National Center for Advancing Translational Sciences as one of the National Institutes of Health’s Clinical and Translational Science Awards, shares a common vision to translate laboratory discoveries into treatments for patients, engage communities in clinical research efforts, and train the next generation of clinical investigators.