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ENGIN Frontier Program on a Precision Path to Epilepsy Treatment
Ethan Goldberg, MD, PhD, thinks that one of the most important discoveries in neurology over the past two decades is that epileptic encephalopathies – the most severe form of epilepsy – are genetic in nature.
“In total, these epileptic encephalopathies are a somewhat rare cause of epilepsy, but we have now identified more than 100 epilepsy genes,” he said. “That said, this sort of explosion in molecular neurogenetic testing hasn't really led to improvements in treatment yet.”
The Epilepsy NeuroGenetics Initiative (ENGIN) is bridging that gap, buoyed by support from the Children’s Hospital of Philadelphia Frontier Program, which directs funding toward CHOP clinical and research efforts showing promise in areas of need. ENGIN aims to expand access to genetic testing to all children with epilepsy and develop individualized treatment plans informed by the latest research advances.
In addition to Dr. Goldberg and Katherine Helbig, MS, LCGC, directors of ENGIN, program leadership includes core faculty members Dennis Dlugos, MD, MSCE; Ingo Helbig, MD; Eric Marsh, MD, PhD; Sudha Kessler, MD, MSCE and Benjamin Kennedy, MD; who are all faculty members of the Perelman School of Medicine at the University of Pennsylvania.
In the age of at-home genetic testing kits, patients and families request genetic testing when standard tests fail to reveal the cause of epilepsy. This desire is not unfounded, as that information can, in some cases, inform medical management, and can educate families as to whether there is a risk to a subsequent pregnancy or if a sibling is a carrier for a neurological disease. However, the journey of epilepsy diagnosis and treatment doesn’t begin with genetic testing; it follows a progressive line of investigation to determine possible cause.
“Many families call this the diagnostic odyssey, referring to the fact that it often takes several years, if not decades, to find a genetic diagnosis for children with complex medical conditions,” Katherine Helbig said. “However, we believe that, in 2020, we can offer our patients more than this. Within ENGIN, our goal is to arrive at answers that do have a meaningful impact, and do so much more quickly.”
The Starting Line
The workup for epilepsy involves gathering a clinical history, a physical examination, electroencephalogram, MRI of the brain and, in some cases, a spinal tap.
"In parallel with that, only selected cases would have typically been referred for genetic testing in the past,” said Dr. Goldberg, who is also an assistant professor of Neurology at the Perelman School of Medicine at Penn. “Our mantra at ENGIN is that every child with epilepsy should be offered genetic testing."
Backed with Frontier Program support, the ENGIN team collaborates with colleagues in CHOP’s Pediatric Epilepsy Program to ensure each patient sees an epilepsy neurogeneticist and epilepsy neurogenetic counselor and is evaluated for genetic testing as part of the standard pathway of care. This entirely new level of care occurs in addition to receiving the highest level of medical management, including potential dietary or surgical therapy in some patients. The ENGIN team aims to communicate the results of genetic testing with the patient’s family and primary neurologist, in the form of a comprehensive report for each patient that presents interpreted genetic test results and makes genetics-first treatment recommendations.
ENGIN builds on neurogenetics expertise that was already in place at CHOP. Four attending physicians from the neurogenetics clinic who have dedicated expertise in epilepsy, Dr. Goldberg, Dr. Ingo Helbig, Dr. Marsh, neurogenetics program lead, and Xilma Oritz-Gonzalez, MD, PhD, a specialist in neurometabolic disorders, are joined by three epileptologists with specialist training in epilepsy genetics, Mark Fitzgerald, MD, PhD, Shavonne Massey, MD, and Colin Ellis, MD, in addition to three genetic counselors who specialize in epilepsy genetics. This team forms the foundation of the multidisciplinary epilepsy-neurogenetics specialty clinic.
In appropriately selected patients, the proportion for whom genetic testing finds a clear answer is somewhere in the range of 30 to 40 percent.
“Establishing a genetic diagnosis is a critical first step towards the ultimate goal of precision medicine in the epilepsies,” Ms. Helbig explained. “Identifying the causative gene not only gives families an answer to the question of why their child has epilepsy, but it also enables research into precision treatments and allows them to engage with advocacy organizations dedicated to specific genetic epilepsy syndromes. Having a name for the condition opens up these doors for many patients and their families.”
However, many patients reach the end of the diagnostic odyssey without a clear answer, so managing expectations is critical.
“Expanding access to genetic testing is more than the actual test — it’s being able to interpret the test results into a clinical context and communicate the result to the family in an understandable way, which takes immense skill and experience,” Dr. Goldberg said. “Our genetic counselors are highly skilled in communicating complex genetic language to people of varying degrees of genetic, medical, and scientific literacy.”
Dr. Goldberg and his team help families understand that even with genetic testing, there’s a possibility that they will find nothing or that the results could be unclear or even raise more questions. But researchers sometimes find an answer by reanalysis with continuously improving technology and new knowledge. For example, a patient may have a mutation not identified as an epilepsy gene at the time of testing, and then two years later, researchers discover the gene is indeed associated with epilepsy.
“We’re going to follow that child over time, and what’s unclear now may become more apparent, once the patient is enrolled in research and their data reanalyzed on a regular basis,” Dr. Goldberg said.
Unique Opportunities for Research
Pediatric epilepsy is a challenging disorder that calls for a multidimensional approach, which the Frontier Program will support as the physicians and scientists of ENGIN work to map more predictable treatment pathways.
“In addition to learning how genetic variation leads to epilepsy, we're learning how the building blocks of the brain underlie normal brain activity,” Dr. Goldberg said. “This line of translational research also offers the opportunity for the two endeavors to inform one another: What we’re finding in the neurogenetics clinic leads to hypothesis-driven research in the laboratory. We’re really starting to see the potential for our research in experimental model systems to return to the clinic and help children with epilepsy.”
ENGIN includes CHOP’s Epilepsy Genetics Research Project to enroll patients for the identification of new genetic causes of epilepsy and for potential involvement in clinical trials of novel or repurposed compounds used to treat specific epilepsy syndromes, while generating model systems for researching and testing novel treatment approaches. As of 2020, this ENGIN-based research study has enrolled more than 1,000 individuals with genetic epilepsies.
Another aspect of ENGIN’s work is partnering with industry to investigate and develop compounds for novel therapeutic use. Dr. Goldberg explained that most commonly used compounds for the treatment of epilepsy were discovered by chance to be anticonvulsive, and the science followed.
“We subsequently discovered that many of those compounds act on ion channels and neurotransmitter receptors, but they’re not specifically designed to target the underlying cause of epilepsy,” Dr. Goldberg explained. “Our approach is to use genetics to establish a proximal cause of epilepsy and then attempt to determine how that genetic change affects how specific proteins function and then how alteration in protein function alters the activity of neurons and circuits.”
An example is a gene that encodes an ion channel through which charged ions such as sodium, potassium, or calcium flow. The charged ions are the basis of electrical activity in the brain, and genetic variants can affect the flux of ions through a given channel.
“If we have a hyperactive ion channel with too much sodium flowing through it and can specifically block that channel, we might be able to more mechanistically approach that individual’s epilepsy,” Dr. Goldberg said.
To best meet the challenge of designing compounds that selectively act on one ion channel versus another, ENGIN has partnered with biotech companies interested in compound development.
“While that level of precision will not be available for every patient, for those patients for whom it is relevant, we will integrate the results of what’s known in the literature combined with our work in the laboratory to offer the referring provider suggestions about drugs to avoid or a drug we think might be helpful,” Dr. Goldberg said. “In dire situations, there could be opportunity for a rational trial of a novel compound or repurposed compound with potential for efficacy. We are just beginning to understand the power of epilepsy genetics and use it to help patients and families.”