Would you like your child or family member with SCN2A related disorders to participate in current research studies? A study might include an online survey or phone interview, past medical records or possible blood tests and other medical procedures.
The FamilieSCN2A Foundation believes research is our best hope for new treatments and eventually finding a cure for SCN2A associated disorders. Your family’s participation can help us reach these goals.
If you are interested in participating in research to help find treatments and a cure for SCN2A, please review the current research projects. These projects help get us closer to understanding this complex sodium ion channel disorder and closer to improving treatments and finding a cure. Participation is completely voluntary for anyone who has been diagnosed with a change in their SCN2A gene.
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Simons VIP Connect is collaborating with Roche Pharmaceuticals to pilot an exciting research opportunity for families with SCN2A gene changes.
The purpose of this pilot study is to gather information about behavior and brain functioning in children and families with SCN2A gene changes and show that this study model works to collect useful information. We are seeking ten families to participate in this initial study. Depending on the outcome of this pilot study, we hope that this or other opportunities will be available to additional families in the future.
Northwestern has been awarded a $12 million, five-year grant from the National Institutes of Health (NIH) to establish an interdisciplinary research center dedicated to advancing the genetic understanding of epilepsy.
The Channelopathy-Associated Epilepsy Research Center, led by Alfred George, Jr., MD, chair and Magerstadt Professor of Pharmacology, will focus on investigating sodium and potassium channel genes, the dominant class of genes responsible for early childhood-onset epilepsy. The center will be made up of a collaborative group of investigators at five academic medical centers, including Northwestern University, three free-standing research hospitals and two industry partners.
Whole-exome sequencing studies of sporadic autism cases have identified SCN2A, which encodes the neuronal voltage-gated sodium channel NaV1.2, as one of the most commonly mutated genes associated with autism. How dysfunctional NaV1.2 affects neurons and consequent circuit function to produce behaviors associated with autism is not well understood.
Geoffrey Pitt and his colleagues at Duke University have recently characterized a familial autism mutation (R1902C) in SCN2A at the structural and biophysical level. This detailed understanding provides a platform upon which to generate a mouse knock-in model, offering a powerful tool for the research community to examine effects at any level — from the atomic (structural) level to behavioral phenotypes — of a monogenic autism mutation.
The researchers propose to generate a mouse bearing the R1902C knock-in mutation within SCN2A (using CRISPR/CAS9 technology) and to characterize the initial physiological and behavioral phenotypes. This mouse model, which will be shared with the research community after initial characterization, will then serve as a substrate for higher-level investigations into how a specific mutation in an autism susceptibility gene leads to the full spectrum of the disorder.
The University of Washington continues to study the phenotype of individuals with Likely Gene Disruptive (LGD) Variants associated with Autism Spectrum Disorder, such as SCN2A. This research study works with families and individuals with these genetic events to try and better understand how these variants impact human development. We focus on the behavioral and medical profiles of individuals with these variants such as SCN2A, and use the same approach in individuals with other disruptive variants so that we can put our findings on SCN2A in context relative to other disruptive variants. We include electroencephalograms (EEG), eye-tracking, behavioral testing, a medical exam, blood draw, and parent testing in order to generate a more complete picture. Research activities can take place at the Bernier Lab at the University of Washington in Seattle, or in the home. We hope to gain a greater understanding of the clinical impact of disruptive variants so we can inform targeted precision treatment options and utilize appropriate outcome biomarkers.
The Bender Lab
The Bender Lab is interested in understanding how loss of SCN2A affects nervous system function at the cellular, network, and behavioral level. Our recent focus has been to understand how SCN2A loss affects the function of neocortical networks in mouse models that either lack one Scn2a gene throughout life or are genetically engineered to delete one Scn2a gene in specific cell classes at specific developmental time points. We hope that these efforts will allow us to determine where and when future therapeutics will have the most benefit.
Post Doc, Dr Joon An is determining the nature and function of the SCN2A mutation in ASD; SCN2A is a gene that encodes a sodium channel that is critical for communication between brain cells, and has been shown to be important for both ASD and infantile seizures. This study will first use an animal model to examine how disruption of SCN2A function at different times in development affects other genes known to play a role in autism. Dr. An will also work with collaborators at UCSF to compare the behavioral and medical features of people with this mutation and autism compared to those without an autism diagnosis. This will help identify the more precise role of this mutation in autism. Eventually, this model could be used to test therapies that might improve symptoms in both people with the SCN2 mutation and those with other causes of ASD.
Nadav Ahituv, Ph.D.
Exome sequencing studies for autism spectrum disorder (ASD) have identified variants in SCN2A as being among the most common risk factors for ASD1. SCN2A encodes the alpha subunit of the voltage-gated sodium channel NaV1.2, which plays a role in neuronal excitability, particularly during early development. Using Scn2a heterozygous mice, the laboratory of Kevin Bender at the University of California, San Francisco have unpublished findings that suggest that Scn2a haploinsufficiency leads to deficits in neuronal excitability during early development, as well as deficits in synaptic function that persist into adulthood. The specific aims of this proposal are:
- Optimize adeno-associated virus (AAV) CRISPRa conditions in mice.In this proposal, Nadav Ahituv plans to use these mice as a tool to test a CRISPR activation (CRISPRa) therapeutic for this gene, upregulating the existing Scn2afunctional copy in these mice and analyzing the phenotypic consequences of this upregulation. Preliminary results from Ahituv’s laboratory suggest that CRISPRa can be used as a therapeutic tool to rescue deficits in Scn2a haploinsufficient mice in vivo.
Ahituv’s laboratory will generate AAV vectors that target Scn2a in mice and optimize the titers, single guide RNA (sgRNA) targets and injection conditions (both location and developmental age) to achieve activation levels in Scn2a heterozygous mice similar to that of wild-type mice.
- Assess the phenotypic consequences of Scn2a CRISPRa. Using the optimized CRISPRa conditions, Ahituv’s laboratory will rescue Scn2a levels in Scn2a heterozygous mice to wild-type levels and determine whether neuronal excitability and synaptic function is restored.
This work will provide insights into the possible therapeutic potential of CRISPRa gene therapy for the treatment of ASDs that are a result of SCN2A genetic mutations. In addition, this mouse model system will allow future testing, via targeted CRISPRa injections into Scn2a heterozygous mice, of the neural and temporal specificity through which SCN2A haploinsufficiency can lead to ASD.
The Stanley Center is actively working on trying to develop compounds that can alter the function of Nav1.2 (SCN2A). The Therapeutics team is currently testing a large number of compounds using a novel technology they have co-developed with an external company to identify compounds that turn up or turn down the function of Nav1.2 to address the loss-of-function or gain-of-function patient populations respectively. The team has also recently characterized a loss-of-function SCN2A mouse model using EEG and are separately characterizing these mice looking at their behavior in collaboration with Harvard's Boston Children's Hospital. This past year Sumaiya Iqbal has created a program which automatically puts all known SCN2A variants onto its 3D structure. Recently Jen Pan and Dennis Lal have been awarded a grant with Al George and a number of other researchers where they will study a large number of SCN2A variants.
Xenon is developing XEN901, a potent, highly selective Nav1.6 sodium channel inhibitor, for the treatment of epilepsy. A randomized, double-blind, placebo-controlled Phase 1 clinical trial to evaluate XEN901’s safety, tolerability and pharmacokinetics is ongoing. Thus far, safety, tolerability and PK for XEN901 are supportive of further development. Xenon expects to test XEN901 in both adult focal epilepsy as well as in SCN8A (Nav1.6) gain-of-function epilepsy (EIEE13), based on feedback from regulatory agencies. Xenon expects to submit a regulatory package to propose development of XEN901 in EIEE13 by the end of 2018.
Nav1.6/1.2 Dual Inhibitors:
Xenon is also developing additional compounds that are potent, selective blockers of both the Nav1.6 and Nav1.2 sodium channels, also for the treatment of epilepsy. These molecules are at the preclinical stages of development and if supported by the preclinical data, a Phase 1 clinical trial could be initiated in the next few years followed by efficacy studies potentially in SCN2A (Nav1.2) gain-of-function epilepsy (EIEE11) patients. Xenon will continue to provide updates as these molecules advance into and through clinical development.
We wanted to let you know that the Simons Foundation Autism Research Initiative (SFARI) had a meeting of funded SFARI investigators recently where leading SCN2A researchers made up one of the featured panels. The talks were given by Raphe Bernier, PhD (University of Washington), Dr. Stephan Sanders, BMBS, PhD (UCSF), Kevin Bender, PhD (UCSF), and Dr. Alfred George, MD (Northwestern University). Each of these scientists gave fascinating updates on their ...innovative work in studying the SCN2A gene and its variants. From creating our children's variants in cell lines, to studying them in animal models, to recording biomarkers and better understand the function - it all leads towards a deeper understanding of SCN2A, new treatments and ultimately a cure.
By establishing an international database of OTs working with SCN2A children, we can begin to define parameters of best practices to ultimately measure effectiveness of therapy and determine multiple ways of supporting children diagnosed with SCN2A. With the scope of data available through therapy sessions, OTs also have the capacity to inform lab research, and to make a real difference not only in the research but in the lives of children and families living with the daily reality of SCN2A.
If your child is working with or has worked with an OT, please enter your email and download the form. Have the therapist fill it out and return it as indicated. If you have worked with an OT in the past OT but are no longer in contact, please complete the form with the therapist’s name and any prior contact information you have, and we may be able to locate them.
To have your child’s occupational therapist participate and register with the SCN2A International OT Database, please visit https://www.otc-frederick.com/scn2a/.
Clinical and genetic spectrum of SCN2A-associated episodic ataxia
Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. This study shows the results of 21 patients with SCN2A-associated Episodic Ataxia, of which 9 are unpublished cases.
Schwarz N et al., Clinical and genetic spectrum of SCN2A-associated episodic ataxia, European Journal of Paediatric Neurology, https://doi.org/10.1016/j.ejpn.2019.03.001 1 March 2019
Published in Trends in Neurosciences | Apr 22, 2018
Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, andintellectual disability.SCN2Aencodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms.
The FamilieSCN2A Foundation works to create, and seeks to enhance a landscape that encourages investment in research by all stakeholders. This includes actively engaging and collaborating with pharmaceutical and biotech companies. The following requirements will help to ensure the highest level of ethical conduct is followed in the organization’s collaborations with these for-profit companies. The goal in engaging companies is to enable the development of therapies to meet patient needs while maintaining independence and neutrality as a patient organization.Download PDF File
- Board Members and members of the Scientific Advisory Committee will disclose any and all relationships with companies with whom the organization engages and will annually sign a statement agreeing to the organization’s Conflict of Interest Policy.
- The organization will collaborate with companies, at its discretion and in consultation with its scientific advisors, which are conducting ethical, high-quality research in a responsible manner, according to industry and international regulatory standards.
- The organization will actively seek the guidance and utilize the expertise of its Scientific Advisory Board throughout the process of working with each company.
The FamilieSCN2A Foundation strongly advocates that all data about a family's medical history, genetic mutation, and all bio-specimens collected (DNA, cell lines, etc) should be in 'pre-competitive' space and should be freely available to any qualified researcher.
This practice helps to amass a large number of families with relevant medical information, which is critical to make progress on any rare disease. It is a strategy used by many other groups and is strongly endorsed by Simons VIP Connect (and made possible by their data platform). This ensures that any researcher with a good idea will be able to design experiments and potentially develop treatments. We are committed for the long term to make all de-identified data and samples available to the research community to make it easier for more scientists to work to find treatments for families. We strongly believe this arrangement is in the best interest of families and the entire SCN2A Community.
To avoid any potential appearance of conflict of interest, Board Members, who have a fiduciary responsibility to the organization and direct the acceptance and use of funds provided by pharmaceutical companies, should not testify at regulatory hearings. Patients and members of the community with a connection to the pharmaceutical company, such as relatives of an employee or owners of stock in the company, should also not testify at hearings.
The organization can accept donations from pharmaceutical companies; however, Board Members and staff may not receive honoraria to speak on behalf of the organization. Travel expenses incurred to participate in disease-awareness activities may be reimbursed directly to the individual or the organization.
Clinical Trial and Approved Therapy Communication:
- The organization will disseminate accurate, fair and balanced information about clinical trials provided by a pharmaceutical or biotech company without additional commentary or opinion that may influence an individual’s decision to participate in a clinical trial or that may change the meaning of the information.
- The organization does not communicate information in a manner that could be interpreted as advertising or promoting a drug or treatment that has not been approved.
The FamilieSCN2A Foundation recognizes the need for open lines of communication, connecting scientists, and forming partnerships with doctors, researchers, and patient organizations which help avoid duplication of efforts. We partner with organizations who share our priorities of finding effective treatments and a cure, and who share our integrity and values that support our mission. Global collaboration will get us closer to a cure of SCN2A related disorders.
Advocacy organizations, medical partners, industry or other parties interested in partnering with The FamilieSCN2A Foundation can contact Leah Schust, President and Founder, for more information.
- Become familiar with your child's genetic change. Learn the terminology (e.g. Missense, Nonsense, Mosaic, DeNovo, Gain of Function, Loss of Function). We can help with this, you can read the publications, speak with a genetic counselor, watch some of the webinars we have on the website, etc.
- Collect your child's medical records and have them organized, preferably scanned or electronic copies. If you have participated in Simons VIP, they can assist you with this process.
- Know your patient rights. If it is not clearly stated on the signed consent form, ask questions about confidentiality and how the data will be used. Will it be returned to you or to SCN2A's central database, Simons VIP? (Did you know that you can request a sample of any bio-specimens, including iPSCs (stem cells) be returned and housed with Simons VIP so other researchers can utilize them?)
- If you are contacted to participate in research and you are unsure about the ethics involved or have not heard about the study through the FamilieSCN2A Foundation, please contact us at Research@SCN2A.org. We can help you determine the legitimacy of the research as well as ensure that all avenues to collaboration are open for the best interest of the community. https://clinicalcenter.nih.gov/…/…/legal/bill_of_rights.html