SCN1A Gene Disorders: Research Update and Personalized ASO Therapy Options
SCN1A mutations are among the most common genetic causes of severe childhood epilepsy, yet 95% of rare disease patients lack treatment options addressing the underlying cause. About 95% of rare diseases have no FDA-approved treatment. Personalized antisense oligonucleotide (ASO) therapy represents a promising path from genetic information to targeted treatment for SCN1A-related disorders. Nome's Patient Journey Platform transforms complex genetic pictures into actionable roadmaps that can guide you to experimental therapies.
Key Takeaways
SCN1A mutations cause a spectrum of seizure disorders, from mild febrile seizures to severe Dravet syndrome, affecting approximately 1 in 15,700 to 1 in 40,000 individuals
80-90% of Dravet syndrome cases are linked to SCN1A mutations, with 90% occurring as new spontaneous mutations rather than inherited
Thousands of SCN1A variants have been reported in public databases; over 1,000 distinct pathogenic or likely pathogenic variants have been curated, requiring personalized therapeutic approaches
Antisense oligonucleotide (ASO) therapies represent a promising approach for addressing the root genetic cause rather than just managing symptoms
Nome's platform synthesizes genetic data and current research to determine ASO therapy feasibility and provide families with clear next steps
What Is the SCN1A Gene and Why Mutations Matter
The SCN1A gene provides instructions for producing the Nav1.1 voltage-gated sodium channel, a critical protein that enables electrical signal transmission in brain cells. This gene is located on chromosome 2q24.3 and contains 26 exons that encode a protein essential for normal neuronal function.
SCN1A's Role in Brain Function
Sodium channels act as molecular gates that control the flow of sodium ions into neurons, generating electrical signals that allow brain cells to communicate. The Nav1.1 protein produced by SCN1A is particularly abundant in GABAergic interneurons—specialized cells that function as the brain's "brakes" to prevent overexcitation.
When SCN1A mutations disrupt these sodium channels, GABAergic interneurons become hypoexcitable, weakening inhibitory control and leading to network hyperexcitability and seizures. This imbalance leads to the neurological symptoms characteristic of SCN1A-related disorders.
Types of SCN1A Mutations and Their Effects
Thousands of SCN1A variants have been reported in public databases; over 1,000 distinct pathogenic or likely pathogenic variants have been curated in relation to seizure disorders, creating a spectrum of clinical presentations. In large cohorts, approximately 40–50% are missense and ~40–45% are truncating (nonsense/frameshift), with the remainder splice-site and copy-number variants; proportions vary by cohort and ascertainment.
Importantly, the type or location of mutation doesn't consistently predict disease severity, as genetic modifiers and environmental factors influence outcomes significantly.
Common SCN1A-Related Disorders: Dravet Syndrome and Beyond
SCN1A mutations cause a spectrum that ranges from relatively mild conditions to severe, life-threatening epilepsies.
Dravet Syndrome: The Most Common SCN1A Disorder
Dravet syndrome represents the severe end of the SCN1A disorder spectrum. Approximately 80-90% of cases are associated with SCN1A mutations, making it the primary genetic cause of this devastating condition.
Clinical presentation:
Seizures beginning in the first year of life, often triggered by fever or elevated body temperature
Multiple seizure types including prolonged convulsive seizures lasting longer than five minutes
Developmental delays and intellectual disability
Movement and balance problems (ataxia)
Behavioral issues including hyperactivity, impulsiveness, and distractibility
Sleep disturbances
Increased risk of sudden unexpected death in epilepsy (SUDEP)
GEFS+ and Milder Phenotypes
Genetic epilepsy with febrile seizures plus (GEFS+) represents a milder presentation where patients experience febrile seizures that persist beyond age six, often accompanied by other seizure types. Some individuals with SCN1A mutations experience only simple febrile seizures, while others develop conditions including familial hemiplegic migraines.
The SCN1A gene has also been identified as a susceptibility factor for common febrile seizures in children without a family history of epilepsy.
Understanding Inheritance Patterns
Approximately 90% of SCN1A mutations in Dravet syndrome are de novo—meaning they occur spontaneously and are not inherited from parents. However, recent research has revealed that some parents previously testing negative actually carry the mutation in a subset of their cells, a phenomenon called mosaicism. This discovery has changed genetic counseling approaches and recurrence risk assessments for families.
Antisense Oligonucleotides: A Personalized Medicine Approach
ASO therapy for SCN1A disorders builds on proven science while enabling unprecedented personalization. Unlike traditional gene therapy that uses viral vectors to deliver functional gene copies, ASOs represent a fundamentally different approach.
What Are Antisense Oligonucleotides
Antisense oligonucleotides are short, single-stranded nucleic acid sequences (typically 15-30 nucleotides) chemically modified for stability and cellular uptake. Common modifications include phosphorothioate backbones (replacing oxygen with sulfur to resist degradation), 2'-O-methoxyethyl (2'-MOE) modifications (enhancing binding affinity), and locked nucleic acids (LNAs) that increase target binding strength. These chemical enhancements allow ASOs to survive in biological fluids and penetrate cells effectively.
How ASOs Correct SCN1A Defects
ASOs can address SCN1A mutations through multiple mechanisms:
Splice modulation: For mutations affecting RNA splicing, ASOs can block aberrant splice sites or promote exon skipping to restore functional protein production.
Steric blocking: ASOs can bind to regulatory sequences and prevent translation of mutant protein while allowing normal protein production from the healthy gene copy.
RNase H-mediated degradation: Some ASO designs recruit cellular enzymes to degrade mutant RNA transcripts selectively.
For Dravet syndrome patients who retain one functional SCN1A copy, ASOs can also upregulate expression from the healthy allele to compensate for the mutated copy's loss of function.
Why ASOs Enable Personalized Treatment
Unlike traditional drugs designed for large patient populations, ASOs can be tailored to individual genetic variants. According to Nome, its AI-powered platform evaluates whether patient-specific ASO therapy is scientifically feasible for individual SCN1A mutations by analyzing dozens of scientific papers and databases.
This personalized approach—sometimes called "n-of-1 therapy"—represents precision medicine at its highest resolution, where the treatment is designed specifically for one patient's unique genetic profile.
Delivery to the Central Nervous System
SCN1A-related seizure disorders require ASO delivery to brain tissue. Intrathecal administration—injection into the cerebrospinal fluid surrounding the spinal cord—has proven effective for other neurological ASO therapies and allows distribution throughout the central nervous system. Treatment protocols typically involve periodic dosing every few months to maintain therapeutic levels.
Current Gene Therapy Approaches for SCN1A Disorders
Several experimental programs demonstrate the feasibility of genetic approaches for SCN1A-related epilepsies.
STK-001: Investigational ASO Therapy
STK-001 is the most clinically advanced investigational ASO for Dravet syndrome, with ongoing/completed early-phase trials assessing safety and preliminary efficacy. This treatment uses a splice-modulating mechanism to increase functional SCN1A protein production from the non-mutated gene copy.
AAV-Based Approaches
Despite SCN1A's size limitations for standard viral vectors, researchers are exploring dual-vector AAV strategies and gene-regulation approaches (e.g., CRISPRa) to upregulate SCN1A; preclinical studies have shown seizure rescue via upregulation.
Individual Patient ASO Programs
Beyond formal clinical trials, some families have pursued individualized ASO development for specific SCN1A variants through collaborations between academic medical centers and manufacturing partners. According to Nome, its platform synthesizes data from peer-reviewed studies, registries, and current trial information to map which experimental therapies match a patient's specific SCN1A variant.
The Science Behind Personalized ASO Design
Creating an effective ASO requires matching the therapeutic strategy to the specific mutation type.
Matching ASO Strategy to Mutation Type
Different SCN1A mutations require distinct ASO approaches:
For nonsense mutations: ASOs may promote exon skipping to bypass a premature stop codon or modulate nonsense-mediated decay; pharmacologic read-through is achieved with small molecules rather than ASOs.
For splice site mutations: Splice-switching ASOs redirect RNA processing to skip mutated exons or restore normal splicing patterns.
For haploinsufficiency: Upregulation ASOs target the healthy gene copy to increase overall protein production.
For toxic gain-of-function mutations: Allele-specific silencing ASOs selectively degrade mutant transcripts while preserving normal ones.
According to Nome, its system analyzes dozens of scientific papers and databases on a patient's genetic mutation to determine ASO feasibility and design considerations.
Navigating the Path from Diagnosis to Experimental Therapy
The journey from receiving an SCN1A diagnosis to accessing personalized therapy involves several critical steps.
Step 1: Genetic Confirmation and Counseling
Comprehensive genetic testing is essential. Genome sequencing provides the most comprehensive analysis; exome sequencing is widely used and often first-line, but may miss noncoding and structural variants.
Genetic counseling helps families understand the specific mutation and its known effects, inheritance patterns and recurrence risks, available reproductive options, and eligibility for research studies and experimental therapies.
Step 2: Exploring Available Research Programs
Families should investigate active clinical trials listed on ClinicalTrials.gov, natural history studies, patient registries, and foundations offering research participation opportunities. However, traditional research programs often exclude ultra-rare variants or lack the operational capacity to develop patient-specific therapies quickly.
Step 3: Understanding the Development Timeline
Traditional drug development takes 10-15 years. For rare genetic disorders, this timeline is incompatible with patient needs. Reported timelines for individualized ASOs range from ~1–3+ years; costs vary widely (often several million USD) depending on design, preclinical work, manufacturing, and regulatory path.
According to Nome, its platform coordinates geneticists, research labs, manufacturers, regulators, and providers—handling operational complexity that would otherwise take years.
Nome's 5-Step Patient Journey:
Start your journey: Share your diagnosis through Nome's secure intake system
Summary Report: Receive a free, AI-generated, expert-reviewed evaluation of custom therapy options
Engage with the team: Live follow-up support to explore what's scientifically possible
Action Plan: Execution-ready, highly detailed next steps tailored to your genetic profile
Ongoing Support: Partnership throughout development, regulatory approval, and treatment delivery
For clinicians, Nome's Provider Platform offers a system to submit genetic test results and receive a concise Provider Brief with prioritized therapy options, mechanism-level rationale, and citations specific to each patient's SCN1A variant.
Current Research and Clinical Trials
The field of SCN1A therapeutics is advancing rapidly, with multiple research initiatives exploring genetic approaches.
Finding Relevant Clinical Trials
Families can search ClinicalTrials.gov for current studies using search terms including "SCN1A," "Dravet syndrome," "antisense oligonucleotide," and "gene therapy."
Important considerations when evaluating trials include eligibility criteria (age restrictions, specific mutation requirements, seizure frequency thresholds), geographic location, study design (open-label versus placebo-controlled), and duration of commitment required.
What Endpoints Researchers Are Measuring
Clinical trials for SCN1A therapies typically assess primary endpoints including change in monthly convulsive seizure frequency; secondary endpoints may include status epilepticus frequency, quality of life, and developmental measures. Additional parameters include biomarkers (electrophysiological measurements or molecular indicators) and safety parameters (adverse events, laboratory values, physical examinations).
According to Nome, its platform synthesizes current trial and program information alongside patient-specific genetic data to identify matching opportunities that families might otherwise miss.
Working with Providers
Medical teams play essential roles in evaluating and implementing experimental genetic therapies.
What to Expect from Your Medical Team
Comprehensive care for SCN1A disorders requires pediatric neurologists or epileptologists (primary seizure management), genetic counselors (interpretation of test results), clinical geneticists (evaluation of complex findings), developmental specialists (assessment and intervention), and research coordinators (clinical trial facilitation).
Questions to Ask Your Neurologist
When exploring personalized ASO therapy options, ask: Is my child's specific SCN1A mutation amenable to antisense oligonucleotide approaches? Are there active clinical trials enrolling patients with this variant? What would be the expected delivery method and dosing schedule? How would we monitor treatment response and potential side effects?
Data Sharing and Privacy
According to Nome, its platform is HIPAA-compliant with Business Associate Agreements ensuring that genetic and medical information shared for therapeutic evaluation remains secure. For clinicians, Nome's Provider Platform provides transparency through in-line citations for every source used to generate reports.
Hope and Action: Real Stories
The path from diagnosis to treatment is challenging but increasingly achievable for determined families. Nome's founder, Stevie Ringel, was diagnosed at seventeen with a rare retinal disease causing progressive blindness. After being told "there's nothing to do," Stevie founded a 501(c)3 organization to develop novel gene therapy and ultimately created Nome to extend this possibility to every family facing a rare disease diagnosis.
One family's 12-year-old child was losing hearing and sight to a degenerative disease. The family spent years collecting conflicting opinions and hitting dead ends. According to the family, Nome's system pulled the whole story together, mapped real options, matched the right partners, and laid out clear next steps.
The Role of Patient Foundations
Patient advocacy organizations provide critical support:
Dravet Syndrome Foundation: Research funding, family support, physician education
SCN1A patient communities via Simons Searchlight: Connecting families with similar mutations
Epilepsy Foundation: Broad resources for all epilepsy types
These organizations help families find expert medical centers, connect with others facing similar diagnoses, access financial assistance, and participate in research advancing treatments.
Nome exists to spread hope to every family who's heard "you have no options," building a world where every patient has a treatment for their disease, no matter how rare the disorder.
Next Steps for Families with SCN1A Mutations
Immediate Actions
Confirm genetic diagnosis: Ensure comprehensive sequencing with proper variant interpretation
Connect with specialized epilepsy centers: Seek expertise in genetic epilepsies and SCN1A disorders
Document seizure patterns: Keep detailed records of seizure types, triggers, and responses to medications
Join patient registries: Organizations like Simons Searchlight SCN1A collect data advancing research
Connect with advocacy groups: Access resources, support, and research opportunities
Exploring Personalized Therapy with Nome
For families interested in pursuing custom ASO therapy:
Submit genetic information: Share diagnostic reports through Nome's secure intake system
Free eligibility assessment: Receive an AI-generated, expert-reviewed evaluation determining if personalized ASO therapy is scientifically possible
Receive development plan: Obtain a comprehensive roadmap outlining therapeutic approach, timeline, partners, and transparent costs
Decision point: Review the plan with your medical team
Ongoing partnership: Nome manages vendor coordination, regulatory requirements, and delivery
The process transforms complex genetic information into clear, actionable roadmaps. Get started today to see what's possible for your family.
Frequently Asked Questions
What causes SCN1A gene mutations and can they be inherited?
Approximately 90% of SCN1A mutations in Dravet syndrome occur spontaneously (de novo) as new mutations not present in either parent. These happen during egg or sperm formation or early embryonic development. The remaining 10% are inherited from a parent who may have a milder condition like GEFS+ or who carries the mutation in only some cells (mosaicism). When one parent has an SCN1A mutation, each child has a 50% chance of inheriting it, though disease severity may vary. Genetic counseling helps families understand their specific situation and recurrence risks.
How do I know if my child is a candidate for personalized ASO therapy?
Candidacy depends on the specific SCN1A variant, mutation type, disease progression stage, and potential for ASO-based intervention. Missense mutations, splice site mutations, and certain nonsense mutations may be particularly amenable to ASO approaches. According to Nome, its free evaluation process analyzes your child's genetic data against current scientific literature to determine feasibility. Generally, children with confirmed pathogenic SCN1A variants who have not yet experienced extensive irreversible neurological damage are stronger candidates, though each case requires individualized assessment.
What is the difference between gene therapy and antisense oligonucleotides?
Gene therapy typically uses viral vectors to deliver a functional copy of an entire gene into cells, permanently adding genetic material. ASO therapy uses short synthetic molecules that bind to RNA and modulate how existing genes are processed or expressed, without changing the underlying DNA. For SCN1A disorders, traditional gene therapy faces challenges because the gene is too large for standard viral vectors. ASOs offer advantages including mutation-specific design, reversible effects (allowing dose adjustment), established CNS delivery methods via intrathecal injection, and regulatory precedent from FDA-approved neurological ASO therapies.
How long does it take to develop a personalized ASO treatment?
Reported timelines for individualized ASOs range from ~1–3+ years from concept to first patient dosing, encompassing design, synthesis, preclinical testing, regulatory filing, and manufacturing. According to Nome, its AI-powered platform compresses this timeline by automating partner matching, coordinating contract manufacturers, and streamlining regulatory pathways. After the initial free eligibility assessment, Nome states it provides a 30-day therapeutic development plan outlining the specific timeline for your child's mutation. The actual duration depends on preclinical testing requirements, regulatory review processes, and manufacturing complexity.
What are the risks and side effects of ASO therapy for SCN1A disorders?
ASO therapies delivered intrathecally (into spinal fluid) carry risks including headache, back pain, nausea, and fever related to the injection procedure. More serious but rare complications include infection (meningitis), bleeding, or nerve damage. ASO-specific effects may include injection site reactions, changes in cerebrospinal fluid protein levels, and potential immune responses. For SCN1A-specific ASOs, theoretical risks include over- or under-correction of sodium channel function leading to altered seizure patterns. All individualized therapies require rigorous preclinical safety testing and careful clinical monitoring under FDA oversight through the Investigational New Drug (IND) process, with clearly defined stopping rules if safety signals emerge.
