Individualized Antisense Oligonucleotides for SCN2A Related Developmental Epileptic Encephalopathy

SCN2A variants are one of the most common genetic causes of intractable epilepsy in children, particularly in developmental and epileptic encephalopathies (DEEs) which can present with uncontrolled seizures at birth, accounting for 1-2% of all epileptic encephalopathies. There is significant genotype-phenotype heterogeneity in SCN2A-related disorders (SRD) which include neurologic symptoms of seizures, developmental delay, choreoathetosis, and autism spectrum disorder (ASD). A substantial fraction of causal variants is gain-of-functon(GOF) or mixed function, functionally associated with increased open-probability or greater sodium current flux. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic SNPs for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Efficacy measures were also individualized to phenotype. Improvements in seizure control, development, and quality-of-life were seen with no ASO-related adverse events. Haplotype phasing in a separate cohort of infants with SRD diagnosed by rapid whole genome sequencing identified 16% of patients with compatible SNPs. Allele-selective ASOs demonstrate potential to decrease seizures and impact neurodevelopment, providing a pathway for potential benefit in n-of-1 to n-of-more SRD patients.