Hemophilia A (HA) is a genetic disorder caused by missing or defective factor VIII, an essential blood-clotting protein encoded by the F8 gene. Individuals with HA suffer from a severely reduced ability to form blood clots, which causes them to bleed heavily from even a slight injury and poses serious medical risk. Currently, an estimated 20,000 people in the United States are living with some type of hemophilia.
More than 1,000 different mutations have been reported in the F8 gene. However, a small but significant subset of individuals diagnosed with HA have a normal coding sequence of the F8 gene, which suggests that other molecular mechanisms, in addition to F8 mutations, might be responsible for FVIII deficiency and blood-clotting disorders. As part of the Center for Biologics and Evaluation Research (CBER) Research Participation Training Program at the U.S. Food and Drug Administration (FDA), Katarzyna Jankowska, Ph.D., investigated non-traditional causes of hemophilia A.
The CBER Research Participation Training Program is one of the Oak Ridge Institute for Science and Education (ORISE) Research Participation Programs at FDA, which offer educational and training programs designed to provide college students, recent graduates and university faculty opportunities to connect with the unique resources of FDA. Jankowska became a fellow in the program after receiving her doctoral degree in biophysics and biochemistry from Rutgers University in 2012 and completing postdoctoral training through laboratories at the University of Pennsylvania and Children’s Hospital of Philadelphia.
For her fellowship, Jankowska was placed at the CBER research facility in Silver Spring, Maryland. Over the course of three and a half years, she collaborated with mentors Chintamani D. Atreya, Ph.D., and Zuben Sauna, Ph.D., to evaluate the effect of microRNAs (miRNAs) on the FVIII encoding gene. Jankowska and her team conducted Next Generation Sequencing studies and a series of cell culture studies to detect and validate miRNAs responsible for FVIII suppression in HA patients with no mutations found in the coding sequence. They hoped to pinpoint the origin of bleeding disorders in patients with an un-mutated F8 gene, because identifying non-traditional causes of hemophilia A could help treatment and management of the disorder.
“We wanted to learn if miRNA can target and regulate FVIII expression and if these miRNA dysregulations can lead to hemophilia phenotypes,” Jankowska explained.
Jankowska’s team identified a group of miRNAs that were significantly upregulated, or overproduced, in HA patients with no F8 mutation. Using a mammalian cell culture system, they demonstrated that these miRNAs reduce FVIII expression and that inhibiting these miRNAs can partially restore FVIII levels. Their findings confirmed the role of miRNAs in FVIII expression and showed that dysregulation of miRNAs may contribute to FVIII deficiency.
Jankowska’s research offers significant value to the HA community. Her findings provide a plausible mechanistic solution explaining why some individuals with no mutation in the F8 coding region still manifest hemophilia A. Her research also has potential therapeutic applications, as controlling the expression level of miRNAs could help modulate the expression level of FVIII in cells.
In addition to HA studies, Jankowska and her mentor Dr. Atreya also assessed novel pathogen reduction technologies for blood safety.
“In the case of pathogen reduction studies for blood safety from infectious agents, the benefit is clear,” said Jankowska. “If we improve the pathogen inactivation methods, the safety and quality of blood and blood product will also improve, which saves lives.”
Jankowska is grateful for her fellowship experience at CBER. She credits her mentors for helping her evolve as a scientist. During her fellowship, she gained exposure to many different areas of research within FDA and learned new laboratory techniques and skills. Some of the research she conducted alongside Dr. Atreya and Dr. Sauna was published in TRANSFUSION and Blood Advances, two well-established hematology journals.
When her fellowship concludes, Jankowska will explore new career opportunities. She hopes to continue contributing to research efforts at FDA and is excited to discover a new project.
“For me, starting a new project is like solving a 10,000-piece puzzle,” said Jankowska. “When you start a new project, you are lost, and you see only some random pieces of information not connected to each other.”
“But every experiment gives new data and new connections. As you collect more and more information you start to fill in the gaps and see the bigger picture. The difference between scientific projects and solving a puzzle is that in science there are always a few pieces missing and there will always be some question to answer,” she said.
The CBER Research Participation Training Program is administered through the Oak Ridge Institute for Science and Education (ORISE) under an agreement between FDA and the U.S. Department of Energy (DOE). ORISE is managed for DOE by Oak Ridge Associated Universities.