August 30, 2022

CURE Epilepsy Discovery: Developing Precision Medicine Treatments for Genetic Epilepsies: Present Challenges, Recent Scientific Advances, and Future Prospects

Key Points:

  • Epilepsy is a serious neurological disorder with many possible causes, and those directly linked to genetic abnormalities have undergone significant scientific breakthroughs in recent years.
  • Precision medicine is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”. This concept is being applied to genetic epilepsies, but significant challenges have limited the rate at which basic science has translated into new treatments.
  • New strategies and scientific techniques may hasten the process. A recent publication in Epilepsia highlights some of them, along with the basic science that has fostered the hope for the eventual realization of precision medicine [1]. The authors suggest that greater coordination of efforts by scientists, physicians, patient advocates, and the federal government will accelerate effective, ethical, and equitable precision medicine for genetic epilepsy.
  • This publication stems from discussions at the Epilepsy Precision Medicine conference, funded in part by CURE Epilepsy and held in Washington, DC in 2019. This conference brought together the many stakeholders involved in developing precision therapies for epilepsy including researchers, physicians, funding agencies, and people with lived experience to share their experiences of epilepsy. The publication’s writing team was led by recent CURE Epilepsy Taking Flight grantee Juliet Knowles, MD, PhD.


Deep Dive:

Epilepsy is a debilitating but surprisingly common neurological disorder, with 1 in 26 people in the United States developing it over the course of their lives [2]. Despite the availability of numerous antiseizure medications (ASMs), one-third of people with epilepsy have seizures that remain treatment-resistant [3]. There are many possible causes of epilepsy, ranging from traumatic brain injuries to specific genetic mutations. Regardless of the cause, treatment remains primarily empirical or based on observation, with patients and their epileptologists often trying different and multiple ASMs in an attempt to eliminate the seizures while managing unwanted side effects. Ideally, treatments for epilepsy would precisely target the underlying biological mechanism, control seizures, and reduce the occurrence of negative side effects.

Optimism for this approach of “precision medicine” for epilepsy grew following the complete sequencing of the human genome and fueled the hope that individual genetic information could be used to develop more specific ways to treat epilepsy. Precision medicine, also known as personalized medicine, is the “tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.” Unfortunately, for most types of genetic epilepsy, the individual genetic makeup of a patient has not yet translated to clinical application of precision medicines for epilepsy. This has been due, in part, to the complexity of the underlying biological mechanisms as well as limitations in the technologies needed to advance genetic discovery to appropriate treatments.

However, the authors describe how epilepsy research is entering an exciting new phase that may enable new precision therapies for many more types of genetic epilepsy. Over the last decade, significant progress in advancing precision medicine approaches has been achieved for epilepsies caused by discrete mutation(s) in a single gene. This work has involved 1) acceleration and efficiency of gene sequencing technology and identification of epilepsy-causing, including the location and type of specific mutations in the DNA sequence of these genes, and 2) clarification of the neuronal function(s)/dysfunction of the corresponding protein and underlying biochemical pathways. In addition, the development of specific laboratory methods such as cell-based models that replicate aspects of the structure and function of the human brain and the use of zebrafish that are sensitive to ASMs have accelerated the testing of novel epilepsy treatments. Finally, new epilepsy gene-targeted technologies, for example, antisense oligonucleotides, are being tested in clinical trials, and there is active discussion about changes in clinical trial design that could enable smaller clinical trials needed for rare genetic epilepsies.

Despite these successes, multiple challenges remain for the future development and accessibility of precision therapies for epilepsy. First, genetic testing and counseling remain inaccessible to many groups, including the elderly and the poor, across the world. Second, nearly 70% of epilepsy cases involve more than one gene and thus require an improved understanding of disease risk in the context of multiple genetic mutations, overall genetic background, and environmental exposure. Third, although gene therapy is conceptually encouraging there are challenges related to large-scale development of safe, ethical, and equitable delivery of gene-based therapies to overcome. It will be critical for the research community to work together to overcome these challenges to ensure the delivery of new precision therapies for genetic epilepsies.

An important driver for the advancements that have been made toward the development of precision therapies are the many new stakeholders calling for action. Numerous patient advocacy groups, professional societies such as the American Epilepsy Society, government and non-profit funding agencies such as the National Institute of Neurological Disorders and Stroke and CURE Epilepsy, respectively, have collectively called for a coordinated and systematic approach to developing new epilepsy treatments. Progress stemming from this call to action could bring a new age of treatments for those with epilepsy, shifting from observational experience to data-driven and patient-centered precision therapy.


Literature Cited:

  1. Knowles JK, Helbig I, Metcalf CS, Lubbers LS, Isom LL, Demarest S, Goldberg EM, George AL, Lerche H, Weckhuysen S, Whittemore V, Berkovic SF, Lowenstein DH. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia 2022
  2. Hesdorffer D, Logroscino G, Benn E, Katri N. Cascino G, Hauser W. Estimating risk for developing epilepsy. A population-based study in Rochester, Minnesota. Neurology 2011; 76:23–27
  3. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs. A 30-Year Longitudinal Cohort Study. JAMA Neurology 2018 75:279-286.