Khoshkhoo Works to Transform Epilepsy Research Through Genetics
When Sattar Khoshkhoo, MD, of the Department of Neurology, looks to the future, he sees exciting opportunities, both in his career and for his field of study. This spring, Khoshkhoo begins his role of principal investigator and launches the Khoshkhoo lab. Simultaneously, research in epilepsy genetics, his area of expertise, is undergoing a dynamic phase as cutting-edge technologies allow researchers to pursue new questions.
Sattar Khoskhoo
As the founding director of the Epilepsy Genetics Clinic, Khoshkhoo hopes to seamlessly blend his roles as a physician and scientist, applying insights from his research to improve the lives of patients with epilepsy. Epilepsy is a neurological disorder marked by recurrent seizures triggered by sudden bursts of electrical activity in the brain. It causes symptoms such as loss of consciousness, focal neurological impairment, and convulsions, complicating daily life.
“I aspire to make epilepsy genetics a routine part of our clinical practice, and to focus on it as an avenue for bringing new treatments to patients,” says Khoshkhoo. “Epilepsy genetics applies to many individuals, is highly relevant to how we take care of our patients and has the potential to revolutionize treatments for patients with epilepsy.”
Shifting the Focus for Epilepsy Research
As an undergraduate at UCLA, Khoshkhoo conducted neuroscience and epilepsy research under the mentorship of Carlos Portera-Cailliau, MD, PhD, a neurologist, and Peyman Golshani MD, PhD, an epileptologist. His interest in the condition grew during his residency, where he saw patients with medication-resistant epilepsy undergoing complex brain surgery. These patients’ experiences, combined with his background in epilepsy research, prompted Khoshkhoo to view the condition in a new light.
“Epilepsy is possibly the longest-studied disease that there is, and the medical field’s fascination of seizures goes back thousands of years,” says Khoshkhoo, who notes that the bulk of previous epilepsy research primarily focuses on neural circuits, neural communication, and ion channels rather than the genetic and molecular pathways behind the disease. “Epilepsy genetics allows us to shift our focus, to examine a very old disease from a fresh perspective.” This new framework is made possible by a boom in genetic sequencing technology, which has only recently become applicable to clinical research.
Khoshkhoo further specialized in epilepsy genetics during his postdoctoral study at Boston Children’s Hospital. There, he identified a critical need for the study of epilepsy genetics in adult patients. “There is an incorrect perception that adult neurologic diseases such as epilepsy have less of a contribution from genetic factors than pediatric neurologic diseases do,” says Khoshkhoo.
His lab is at the forefront of studying the genetic basis for adult epilepsy, filling a crucial gap in research. “We have up to seven decades worth of patients with epilepsy who have transitioned to the adult world before genetic sequencing and screening was even being done on the pediatric side.”
Current Investigations
Currently, Khoshkhoo is investigating somatic mutations that may contribute to epilepsy in adults. These mutations, which are acquired during development and are present in only specific parts of the body, are a factor in many adult neurologic diseases, including focal epilepsy, a form of epilepsy where seizures are localized to a specific part of the brain, rather than the entire brain. “Identifying and diagnosing diseases caused by somatic mutations is particularly challenging in clinical settings,” Khoshkhoo explains. “As a result, they haven’t received much focus or discussion.”
Focal epilepsy is the most common type of epilepsy in adults and can become drug resistant and hard to treat with medications alone, often resulting in the need for surgery. Most cases of focal epilepsy involve seizures starting in a part of the brain called the mesial temporal lobe. This area is important for learning, memory, and managing emotions. Much of Khoshkhoo’s research focuses on understanding the specific genetic mechanisms in the brain that cause mesial-temporal lobe epilepsy.
One such genetic mechanism is the Ras-MAP Kinase signaling pathway, a molecular pathway in our cells that plays a role in cell growth, division, and survival. The proteins involved in the pathway operate like a series of switches, turning these cellular functions “on” and “off” in response to signals from outside the cell such as hormones, neurotransmitters, and growth factors. Khoshkhoo’s team recently discovered that mesial temporal lobe epilepsy may be caused by mutations that activate the Ras-MAP Kinase signaling pathway.
“The Ras-MAP Kinase pathway appears to play a pivotal role in driving mesial temporal lobe epilepsy in a significant subset of patients,” says Khoshkhoo. “Interestingly, this pathway happens to be one of the most studied pathways in the context of cancer, with numerous drugs and clinical trials dedicated to it. However, the potential to treat neurological diseases by targeting the Ras-MAP Kinase pathway has been overlooked.” If preclinical models demonstrate the efficacy of these drugs in epilepsy, there’s potential for repurposing them to benefit patients with epilepsy.
Linking Research and Clinical Practice
Khoshkhoo’s long-term objective is to apply his research and progress in epilepsy genetics to clinical practice. Recent advances suggest that he may soon realize this goal.
“I think we are in the infancy of clinical trials for gene therapies targeting epilepsy. In the next five years or so, there will likely be numerous opportunities for clinical trials, offering targeted treatments to patients who previously lacked such options,” says Khoshkhoo. “Additionally, there are many drugs currently in development tailored to specific syndromic epilepsies that our adult patients could also benefit from.”
Through his involvement with the Brigham’s Epilepsy Genetics Clinic, Khoshkhoo is preparing patients for future advancements in the field. “It is important to identify patients who might be eligible for these treatments now so that when those clinical trials become available, it will be very easy for them to enroll,” notes Khoshkhoo. “We have created a center where we have the ability to make those critical diagnoses and where we can channel our patients to specific, ongoing or up-and-coming trials, allowing them to get the specialized, targeted care they need.” Additionally, the clinic collaborates with other physicians to bring cutting-edge care to patients with epilepsy, taking referrals, facilitating genetic testing, and, if needed, guiding individuals to specialized treatment for their underlying conditions.
Hopes for the Khoshkhoo Lab
While Khoshkhoo aims to make a wide-reaching impact on research and clinical practice for epilepsy and other neurological diseases through the work of his lab, he also has hopes for his lab on a much smaller, but no less significant, scale.
“I’m hoping that we can create a lab that not only has a sustainable culture of excellence, but also it is a place where people thrive, enjoy what they’re doing, and understand the impact of their work,” says Khoshkhoo, who strives to step into a role as a mentor for his lab.
“The impact that I make as an individual will likely be small compared to the impact made through my training and mentoring others over the years,” Khoshkhoo explains. “My mentors have made a really big impact on my career path, and I hope that is something I can carry forward.”