Targeting Genes to Develop New Treatments for Blood Disorders
Dr. Vijay Sankaran discusses recent developments in the treatment of sickle cell disease and other blood disorders.
Published August 16, 2017
In 1973 the lifespan of a person with sickle cell disease (SCD) in the United States was 14 years. Today, the lifespan of a person with SCD has increased to 40-60 years. While diagnosis and care for people with SCD has improved, treatment options remain limited. In fact, before the recent approval of Endari there was only one FDA approved treatment for SCD, an inherited red blood cell disorder where red blood cells become rigid and sickle shaped impeding the flow of blood and oxygen through the body’s blood vessels. Still, insights into the pathophysiology of SCD and other blood disorders has led to promising new treatment approaches. At the forefront of this research is Dr. Vijay Sankaran an Assistant Professor of Pediatrics at Harvard Medical School and Attending Physician in Hematology/Oncology at Boston Children’s Hospital and the Dana-Farber Cancer Institute.
Dr. Sankaran’s research into inherited blood disorders was inspired by his initial work in understanding the mechanisms behind fetal hemoglobin regulation. During gestation the fetus expresses a form of hemoglobin that helps extract oxygen from the mother. After birth this mechanism is silenced and fetal hemoglobin is no longer produced. People with SCD could benefit greatly from the continued production of the fetal form of hemoglobin. As he explained, “We knew that patients with a number of inherited blood disorders such as SCD and beta-thalassemia can actually do much better if they have higher levels of fetal hemoglobin. There were clear indications that inducing fetal hemoglobin could be effective, but we lacked the tools to reactivate fetal hemoglobin in adults.” This line of research eventually led Dr. Sankaran to identify and demonstrate that the BCL11A gene is a potential therapeutic target. BCL11A could be induced to produce fetal hemoglobin, which would produce healthier red blood cells and fewer sickled cells.
Related to Dr. Sankaran’s research into activating the BCL11A gene in adults is his research into the regulation of blood production more generally. For example, work from his group has shown that shutting down the SH2B3 gene which, “normally functions as a break on red blood cell production,” could be valuable for, “applications where people are interested in trying to produce blood cells outside of the body for transfusion or other purposes.” If the SH2B3 gene “break” was removed more healthy red blood cells could be produced. This is tremendously important for people with SCD because, “Many of them cannot tolerate the blood from most donors, because they have developed antibodies against the donor’s blood antigens.” His research on the SH2B3 gene could lead to less expensive and more widely available methods for manufacturing red blood cells.
The cost and time associated with the research and development of new treatments is immense and the length of the development pipeline represents a significant clinical challenge. As an example, Dr. Sankaran noted how the development of Endari began three to four decades ago. But, he believes these challenge can be overcome, “Using insights from human genetics and natural observation, can help in the development of new treatments for SCD. For many years it was unclear what clinical endpoints would be ideal to go after in SCD. There are many manifestations, but the more candidate therapeutics we identify, and the more clinical trials we perform, we can better learn how to measure the effect of these endpoints.”
Finally Dr. Sankaran offered some advice to future researchers, “I think the key is to not be afraid to take risks. It’s critical to find not just a single mentor, but many mentors to help shape your career. Find and talk to a number of mentors who can help guide you. Sometimes it’s very easy to lose focus in an area. I was very lucky as a graduate student to work with Stuart Orkin, who allowed me to take some risks and pursue research into fetal hemoglobin. I then continued this research as a post-doctoral fellow with Eric Lander at the Broad Institute and Harvey Lodish at the Whitehead Institute, while David Nathan and Sam Lux – among others – at Boston Children’s have helped me to develop as a clinician as well to make sure the work we pursue in the lab relates to the patients I care for.”
Hear more about the latest advances in the treatment of sickle cell disease from Vijay Sankaran, MD, PhD and others at “Towards Transformative Therapies for Sickle Cell Disease.” Additional information about the event can be found here. Abstract submissions for a poster session (of which two will be chosen for a short talk) will be open until Friday, August 25.