Report on Second Scientific SCN8A Conference
Hosted by Wishes for Elliott
SCN8A SCIENTISTS GATHER TO STRATEGIZE ON ACCELERATING PROGRESS
Wishes for Elliott was honored to host a second gathering of SCN8A researchers and clinicians, the New Developments in SCN8A Conference, from around the globe on December 1, 2016 in Houston. Over 50 researchers participated, openly sharing directions and challenges of their ongoing work and engaging in an “outside the box” exploration of strategies for accelerating the pace of answers for SCN8A children and their families.
One major milestone occurred before the meeting even began – 83 (out of 102 invited) families participated in a survey on their child’s condition, experiences with medication, challenges with medical care, and priorities for future research. While clearly limited in its depth, this survey provides researchers the most comprehensive profile ever of SCN8A children – and whet their appetite for probing some of the new mysteries revealed.
The widespread interest in participation – by a wide range of leading scientists, the two Young Investigators who were awarded grants by Wishes for Elliott, and the team at Xenon working to develop SCN8A-specific medications – forced us to switch locations to find a room large enough to accommodate the growing number of researchers studying SCN8A.
New Findings from Family Survey
Of the 83 respondents, only 25% have effective control of seizures – with nearly double the observed rate from broader populations being “refractory” or unresponsive to anti-epileptic drugs (AEDs). This demonstrates what we already believed to be true, that SCN8A is a particularly severe form of epilepsy.
Of the 24 AEDs reportedly used by the respondents, 20 had completely opposite effects on different children i.e. were effective in improving seizure control in some while totally ineffective in others. Our population is extremely heterogeneous with no AED uniformly effective among our children.
Many, but not all children, experience serious developmental delays or even an absence of development: 52% cannot walk, 40% have limited manual dexterity, 40% cannot sit independently, and 30% do not have neck control. The most pervasive problem is with speaking – only 16% speak well, with 64% being non-verbal. Once again, significant diversity within the population, but most children experience some delays.
New and important information was disclosed regarding an apparently very high correlation between the location of some mutations and the impact of the children’s seizure control or development. Of the five reported cases of children over 2 years old with mutations at R850Q and N1877S, the former were 100% refractory and experienced limited development while the latter group were 100% seizure free and experienced no developmental delays in sitting, manual dexterity or walking (although about 10% of the children with mutations at N1877S experience some limitations in speech development). In the former, seizures appear between 0-5 months with nearly ½ experiencing infantile spasms, while the latter group had seizures first emerge at 5-10 months and none experienced infantile spasms. This striking new data suggests several areas for promising future research on understanding how the mutations at different locations function and lead to dramatically divergent results.
Conference Presenters (slide decks will be shared as approved)
Ingo Helbig, author of the scientific blog on epilepsy and genes, “Beyond the Ion Channel,” pediatrician and child neurologist at CHOP, spoke about the opportunity to harness the enormous potential of the internet to increase the pace of scientific progress.
Ted Cummins, with a long career focusing on sodium channel biophysics, and having characterized the first ion channel disease variant of SCN4a in 1993, discussed his ongoing study of cannabidiol to attenuate resurgent current in Nav 1.6 channels.
Christopher Mackinson, a recipient of a postdoctoral fellowship from Wishes for Elliott, spoke about development of a cutting-edge, three-dimensional structure to study mutations in the SCN8A gene.
Andrew Tidball, also a recipient of a postdoctoral fellowship from Wishes for Elliott/AES discussed his work using gene-editing techniques to generate isogenic controls and “virtual” patient iPSC cells to test new drug treatments for SCN8A patients.
Miriam Meisler, the matriarch of SCN8A with her students and mice widely populating the community, discussed her exploration of the underlying pathogenicity and potential therapies for SCN8A encephalopathy using a “knock-in mouse” expressing the SCN8A-N1768D mutation using TALEN targeting.
Jacy Wagnon, a Research Investigator at the University of Michigan, discussed her ongoing work leading the SCN8A mouse project including molecular, physiological, and behavioral assays to better understand the etiology of SCN8A encephalopathy and to identify novel therapeutic targets.
Jennifer Kearney, a neuroscientist with the Department of Pharmacology at Northwestern, discussed her work on identifying genetic factors that contribute to childhood epilepsy, understanding how they contribute to the underlying pathophysiology, and translating this knowledge into better treatments for refractory epilepsy.
JP Johnson, Director of the Cellular and Molecular Biology Department at Xenon Pharmaceuticals, discussed Xenon’s preclinical discovery effort targeting inhibitors of NaV1.6 channels for epilepsy and efforts to begin testing specific new treatment for SCN8A epilepsies.
Manoj Patel, who directs his own electrophysiology laboratory at the University of Virginia and focuses on understanding the importance of the sodium (Na) channels in the development of epilepsy, discussed his recent focus on the mechanism by which Nav 1.6 gain-of-function and loss-of-function mutations can lead to abnormal sodium channel activity and epileptic encephalopathy.
Lori Isom, Chair of the Department of Pharmacology and Professor of Neurology at the University of Michigan, whose laboratory focuses on voltage-gated sodium channel structure, function, and roles in epileptic encephalopathy, discussed her ongoing work studying cardiac arrhythmia in a mouse model.
Identification of Strategies for Accelerating Progress – and Shared interest in Collaborating to Move Forward
Not only were the presentations significant in advancing the technical dialogue among researchers, but the meeting peaked when all the scientists actively engaged with the central challenge of the conference – to identify strategies for accelerating the pace of progress. Participants collectively explored innovative strategies to more rapidly bring answers and better treatments for the rapidly growing number of children struggling with diverse effects of SCN8A mutations.
A number of broad areas for future efforts to accelerate the pace of progress were identified and the commitment to developing a working group to more collaboratively tackle research questions was evident.
There are a lot of exciting new initiatives in the work for Wishes for Elliott as well. We are making great progress in exploring the possibility of utilizing a biodata bank at the next gathering of families. This would to allow genetic samples to be collected from families in order to expand the possibilities for research and to help prepare the SCN8A community for clinical trials – which we hope aren’t too far down the road!
We have some exciting new partnerships in the works to move beyond standard methods of scientific and research collaboration that hold great promise for learning from other similar disease populations.
Thank you for your support in helping us carry out this amazing conference and continuing to support our innovative and exciting work!