NOLA.The American Epilepsy Society (AES) has wrapped up its annual meeting, which was held this year in New Orleans. AES is the largest meeting of epilepsy professionals working in clinical practice, academia, industry, and advocacy. It is a meeting I always look forward to as an opportunity to connect with friends and colleagues from across the world. As we all pack away our beads and digest our beignets, I would like to reflect on some of the major messages I, as an epilepsy genetics clinician and researcher, took away from this year’s AES annual meeting.Moving from gene discovery into therapeutics. Dr. Lori Isom from the University of Michigan presented extremely promising data in collaboration with Stoke Therapeutics using Targeted Augmentation of Nuclear Gene Output (TANGO). This method increases SCN1A expression by targeting an alternatively spliced SCN1A exon that leads to the incorporation of a premature termination codon and non-productive mRNA product. Dr. Isom and team tested an antisense oligonucleotide (ASO) that targets this alternatively spliced exon in cell and mouse models of Dravet syndrome. A single ASO dose in mice not only increased wildtype SCN1A mRNA expression to levels comparable to wildtype mice but also rescued the SUDEP phenotype. These data are exciting and suggest that we may be on our way to targeted therapies in humans for Dravet syndrome. These findings also suggest that similar mechanisms may be usable in other genetic epilepsies and neurodevelopmental disorders.
Don’t “reinvent the wheel.” Following on from the previous point, it became apparent that if we want to move forward with a clinical trial in any of various genetic epilepsies, an understanding of the natural history of the disease as well as meaningful clinical outcome measures are crucial. “Natural history” in the epidemiological sense is difficult, if not impossible, to achieve for genetic epilepsies and neurodevelopmental disorders, but a baseline understanding of the spectrum of disease is important. We also need to understand what clinical impact we hope to make through a clinical trial. In many cases, seizure outcome is not the most meaningful outcome to measure. How can we capture improvements in development, movement disorders, cognition, etc. in our patient populations? These are questions that all genetic epilepsies are grappling with right now, mostly in isolation. Ideally a unified approach can be developed and we can find a way to move forward united as a community so that we aren’t “reinventing the wheel” each time a new trial comes up.
Making more room at the table. I think we may say this every year, but I love that at each AES meeting new family and advocacy organizations have a presence in the exhibition hall and symposia surrounding the meeting. This year we welcomed SLC6A1 Connect to the stage and were honored to be part of a daylong symposium dedicated to understanding clinical, genetic, and functional aspects of SLC6A1-related disorders, as well as potential venues for future research and therapeutic targets. This is truly a case of building a longer table and mobilizing the epilepsy community to tackle issues related to newly discovered genetic neurodevelopmental disorders. I can’t wait to see what new family organizations we meet next year.
Genetic causes are important. Most obvious statement of the year on the blog? Possibly. But Dr. Joe Symonds’ study nicely highlights the importance of a genetic diagnosis in young children with epilepsy. Dr. Symonds’ prospective study captured all patients under 3 years of age who were newly diagnosed with epilepsy in Western Scotland over a three-year period. Dr. Symonds and his team prospectively performed epilepsy gene panel testing in all children with a new epilepsy diagnosis, along with detailed phenotyping. The study showed that 32% of children with epilepsy beginning before the age of 3 years of age had a genetic cause, 24% had a structural cause, and 4% had a metabolic cause. These prospective, population-based data further emphasize the importance of genetic testing in the workup of new-onset epilepsy in children.
Collaboration, collaboration, collaboration. This is another common message, but it rings true after every meeting. If we are going to successfully tackle the issues facing genetic epilepsies and translate them into meaningful treatments for patients and families, collaboration among researchers, clinicians, industry, and advocacy groups is essential. Open sharing of data is becoming more standard, and I am heartened to see advocacy and family organizations being brought to the table as equal stakeholders. I hope the momentum continues as we move into 2019.
Thank you to everyone who made AES 2018 a great meeting. I look forward to productive collaborations in 2019 and hearing about all our progress in Baltimore!