Kevin Bender

Bender Lab, UCSF

SCN2A loss of function, where a child has too little SCN2A, can lead to life-long difficulties in executing complex tasks. The first goal of this project is to determine whether similar difficulties can be observed in mice with Scn2a loss of function. Furthermore, we will evaluate whether deficits in these behaviors, as well as others we are exploring in the lab, are rescuable with gene therapy approaches that restore Scn2a levels to those found in neurotypical children. Here, our goal is to evaluate these therapies across a range of ages, with the goal of determining which aspects of behavior can be rescued later in life. This will help us understand developmental windows of opportunity for future clinical trials in children and, potentially, young adults.

Yang Yang

Yang Lab, Purdue University

Hundreds of different SCN2A genetic variants have been identified in children with autism or epilepsy. While some of them could be grouped into gain-of-function or loss-of-function variants, others are more complex. In particular, a splice-site variant of SCN2A has been identified in a child with autism. However, how this variant affects the Nav1.2 channel and neuronal activities is completely unknown, hindering the development of targeted interventions. The recent molecular and genomic revolution, including CRISPR-based genome editing technologies, offers enormous promise for treating genetic disorders like SCN2A-related disorders in an n=1 precision medicine manner. Funded by this inaugural Hodgkin-Huxley Research Award, Yang's lab will establish human-induced Pluripotent Stem Cells (hiPSCs) and rodent models of this SCN2A splice-site variant to understand disease mechanisms with clinical translation in mind. Disease phenotypes and global gene expression profiles will be studied to inform drug discovery. Yang lab will also develop cutting-edge gene therapy interventions aiming at correcting this SCN2A genetic variant in tiered model systems to bolster the translation potential of these transformative interventions. Moreover, Yang lab will be exploring next-gen chimeric mouse models with human cells to uncover in vivo phenotypes of human cells carrying SCN2A genetic variants to further increase the predictive value of preclinical disease models. These initial studies are expected to pave the way toward the ultimate clinical translation of promising interventions to improve the quality of life of individuals affected by SCN2A-related disorders.

Rikke Steensbjerre Møller

Danish Epilepsy Centre, Filadelfia/University of Southern Denmark

Bridging the gap between ongoing knowledge and clinical practice – establishment of an international SCN2A database

The aim of this collaborative project between Rikke Møller's and Dennis Lal’s research teams is to establish and maintain an international SCN2A database that can be used to study genotype-phenotype relationships in SCN2A-related disorders. The database will help to record the number of individuals per pathology as well as their distribution. Furthermore, data from the database can help describing the natural history of SCN2A-related disorders, identifying outcome measures and put the basis for drug trial readiness. The specific aims of the study are: 1) To establish and maintain a database including clinical, genetic and epidemiological data of all published individuals with SCN2A-related disorders 2) Assess all reported variants and classify according to the American College of Medical Genetics and Genomics guidelines and 3) integrate all data in the existing SCN portal (scn-portal.broadinstitute.org) – an interactive website designed to provide updated and comprehensive information on SCN2A-related disorders.

Xiaoling Chen, Ph.D. & Jingliang Zhang, Ph.D.

Purdue University

In children carrying SCN2A variants, impaired motor function, repetitive behaviors, social deficits, and altered sensitivity are physiological hallmarks. However, the basic cellular mechanisms that underlie these altered behaviors remain largely unknown. Xiaoling Chen, a postdoc researcher in the Yang lab, is investigating Scn2a-related disorders using in vivo calcium imaging of freely moving mice as well as brain organoids derived from human induced pluripotent stem cells. Funded by the Action Potential Award from the FamilieSCN2A Foundation, Xiaoling’s research aims to identify novel cellular targets for the development of next-generation interventions to alleviate behavioral impairments of affected children carrying SCN2A variants.

Roy Ben-Shalom Ph.D., Assistant Professor

UC Davis MIND Institute / UC Davis Health Department of Neurology

The SCN2A gene encodes the neuronal sodium channel Nav1.2, which is critical for the electrical activity of many types of neurons. Mutations in the gene alter the properties of the NaV1.2 channel, disrupting the function of single neurons and potentially leading to abnormal neuronal circuitry. Ultimately, these effects lead to epilepsy and/or ASD in affected patients. In this proposal, I will explore how alterations to the NaV1.2 channel affect the function of single neurons. Using computational models that simulate neuronal activity, we will study how each variant modulates single neuron activity and then simulate different drugs to see if they can reverse those effects.

Utilizing computational models to simulate the effects of SCN2A variants on neuronal excitability and testing potential therapeutics

Chenyu Wang, MS

UCSF / Bender Lab

NaV1.2 sodium channels encoded by SCN2A are expressed throughout the brain. One region where NaV1.2 channels are expressed at very high levels is the cerebellum. The cerebellum is involved in motor control, motor learning, and—recently identified—various aspects of social interaction typically seen in children affected by SCN2A-related disorders. With the help of the FamilieSCN2A Foundation, our goal here is to understand how cerebellar function is altered in mouse models that lack one Scn2a allele, which models aspects of loss-of-function in SCN2A. In doing so, we hope not only to gain a better understanding of how SCN2A-related disorders affect the brain, but also to develop quantitative biomarkers that can be utilized to evaluate therapeutics.

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★ $50,000 – Research Grant (1 year project)

★ Understanding cellular and behavioral effects of Scn2a haploinsufficiency in cerebellar circuits

Muriel Eaton

College of Pharmacy, Purdue University / Yang Lab

SCN2A variants affect children in a variety of ways. In particular, SCN2A loss-of-function or nonsense variants, which lead to SCN2A deficiency, are strongly associated with neurodevelopmental disorders such as autism spectrum disorder (ASD). Yang lab has been working on a novel Scn2a deficient mouse model, aiming to study mechanisms underlying Scn2a deficiency and test for novel interventions. Muriel Eaton, a PhD candidate in Yang lab, has been exploring the Scn2a-deficient mouse model during her training, and already discovered many characteristics of this mouse model including profound social deficits and other neurodevelopmental abnormalities. For the next phase of their research, they will study how to reverse Scn2a-deficits in the mouse model and to develop potential gene therapy for SCN2A-related disorders, thanks to research funding particularly this grant from FamilieSCN2A Foundation.

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★ $50,000 – Research Grant (1 year project)

★ Advancing gene therapy in a preclinical mouse model of SCN2A deficiency

Eduardo Pérez-Palma, PhD

Genomic Medicine Institute, Cleveland Clinic / Chile

"Our lab focuses on the study of the genetics underlying epilepsy and neurodevelopmental disorders. We study which genetic variants can cause disease and how they can drive disease prognosis, comorbidity, and drug response. Specifically, our research aims to: 1) Unveil the effect of common, rare and structural genetic variation in cases and controls collected from an international collaborative network. 2) Develop tools for variant interpretation by integrating large scale data derived from patients and the general population. 3) Study epilepsy and neurodevelopmental disorders presentation in Latin America. South American countries have a higher prevalence of epilepsy, yet they are underrepresented in current genetic studies. We study Mapuche individuals, Chilean epilepsy cases and controls and patients with SCN2A-related disorders. Overall, our lab is growing a research profile focusing on interdisciplinary genomics and data science to bridge novel genetic knowledge with clinical practice – paving the way for personalized medicine with a particular focus on Latin American populations".

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★ $50,000 – Research Grant (1 year project)

★ Integrating clinical and genetic variables to model SCN2A variant pathogenicity and outcomes

Sunita Misra, MD, PhD

Northwestern University / Lurie Children’s Hospital

*UPDATE December 2019*
In the past, anticonvulsant medications have not been tested for seizure reduction in mouse models of genetic epilepsy. Instead pre-clinical medication trials look at reduction of seizures induced with chemical or electrical stimulation. Recently Dr. Jennifer Kearney's lab at Northwestern University made a new mouse mode of SCN2A-related epilepsy. As part of her FamilieSCN2A Foundation Action Potential Grant, Dr. Sunita Misra is studying seizures in this new mouse model. Sunita's ongoing work shows that seizures in the new Scn2a mouse model are different than seizures caused by chemical or electrical stimulation. These differences may partly explain why many children with SCN2A-related early onset epilepsy have seizures that are difficult to control with current anticonvulsant medications. Further work will look at the effectiveness of FDA approved anticonvulsant medications at blocking seizures in the SCN2A mouse model.

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★ $50,000 – Research Grant (1 year project)

★ Downstream Effects of SCN2A-Related Epilepsy

SCN2A dysfunction changes the way brain cells communicate both electrically and chemically leading to epilepsy and neuropsychological comorbidities. I will use EEG to identify seizure patterns and the role of sleep on seizures in a new mouse model of SCN2A-related epilepsy. Then I will look at neurotransmitter levels in the brains of mice with SCN2A-related epilepsy. I will use drugs that target the abnormal neurotransmitter levels to improve abnormal electrical and chemical signaling in the brain. This work may identify new druggable targets for better control of epilepsy and associated comorbidities in SCN2A-related epilepsy.