Inside the Lab with Davut Pehlivan, MD
Davut Pehlivan, MD, Instructor of Neurology at Texas Children’s Hospital, studies translational neuroscience because of the kids with brain disorders he has seen in the clinic.
Pehlivan first encountered some of these kids during his pediatric neurology rotation at the University of Istanbul School of Medicine in his native Turkey. He felt devastated by their suffering and the fact that little could be done for them. All he or any physician could offer was supportive care because knowledge of their diseases just didn’t exist.
“They [the physicians] didn’t know what they were treating…[because for most] of the syndromes, the genetic etiology [the genetic origin of the disease] was unknown,” Pehlivan says.
Today, we know the genetic cause of almost 35-45% of all genetic disorders. Unfortunately, not much has changed on the treatment front.
Thanks to a $250,000 Mentored Training Fellowship award he received from International Rett Syndrome Foundation, Pehlivan can work on improving this situation.
Pehlivan’s Biomarker Research
One of the main studies Pehlivan is performing with the guidance of his current mentor Huda Zoghbi, MD, is in biomarker identification, an area of research that can greatly facilitate the development of safe and effective treatments.
Biomarkers are indicators of the presence of a disease. A patient’s individual biomarker levels can be assessed by a simple blood or cerebral spinal fluid (CSF) test. Biomarker measurements thus provide an easy way for clinicians to determine the optimal dose for an individual patient’s therapy. For example, the levels of the biomarker cholesterol in a patient’s blood are routinely considered in the design of a personalized heart disease treatment.
Currently, there are no biomarkers for any neurodevelopmental disorder, and any biomarkers Pehlivan develops through his research would likely be the first of their kind. When emerging therapies that target the genetic cause of developmental brain disorders enter clinical trials, having a biomarker that reliably indicates disease severity and response to treatment could prove essential for addressing the variability in each patient’s needs. This is particularly true for Rett syndrome and MECP2 Duplication Syndrome (MDS), the focus of Pehlivan’s research. While the cells of patients with Rett syndrome don’t have enough MeCP2, the protein encoded by the MECP2 gene, the cells of MDS patients have too much of it. Special care must be taken in therapies that target MECP2 to make sure the cells of patients with these disorders end up with healthy levels of MeCP2. Additionally, biomarkers could provide an early indicator of treatment response and enable any needed dose adjustment mid-treatment schedule. Otherwise, it will take the months to years required for changes in the brain to take place to determine if and how well a treatment is working.
Pehlivan is also working on the genetics aspect of MDS and Rett syndrome. Using his background as a geneticist, he is applying the most advanced genetic technologies to understand the MECP2 gene region and whether the genetic structure of this region contributes to disease severity. He strongly believes that the genetic studies he conducts will greatly improve our understanding of Rett syndrome and MDS.
Research Challenges and Ideal Outcomes
To date, Pehlivan and his collaborators have discovered some candidate biomarkers using a method that allows them to compare the content of blood samples collected from healthy patients to those with MDS. Both he and Zoghbi think, if validated, these potential biomarkers could benefit patients with either MDS or Rett syndrome. Pehlivan’s current work will hopefully obtain this clinical benefit. However, he must overcome a significant challenge.
Because Pehlivan studies a rare disease, finding patient volunteers for his studies can be very difficult.
“More [MDS] families are needed [to participate in research studies]…because that is how we can make progress,” says Pehlivan, “We are on the right path, but we need…more samples.”
Pehlivan plans to continue this research and overcome this challenge or any other he encounters in the future. Seeing “the need in parents’ eyes” and “their desire to move this forward” provides him with strong motivation. He is excited about the progress his research has made so far. He expressed optimism about the future of his work and its potential to lead to substantial improvements in the lives of patients with MDS and Rett syndrome since he can focus on this research.
His mentor, Huda Zoghbi, MD, Director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, shares Pehlivan’s outlook on the future of his research.
“Davut is committed to clinical research on Rett syndrome and related MECP2 disorders. Thanks to the IRSF fellowship support, he has been able to immerse himself in clinical trial readiness studies and to commit the needed time [for this research],” Zoghbi says, “His dedication and energy are truly admirable, and I know he will contribute to Rett syndrome clinical research in a most meaningful way.”