Individualized ASOs were designed for two patients with intractable epilepsy with GOF and mixed GOF/LOF causal variants associated with DEE11. Whole genome sequencing identified SNPs on the reference haplotype allowing the design of ASOs targeting only the pathogenic haplotype.

Research investigational new drug applications were authorized by the FDA for investigator-initiated, open-label, single center, single patient (n=1) clinical trials for distinct pathogenic SRD variants with predefined safety and efficacy measures tailored to individual phenotype. The allele-selective ASOs were delivered intrathecally by lumbar injection in these two first-in-human clinical trials. Each trial was customized to the patient-specific SRD phenotype with predefined outcomes measures assessing seizures, behavior, communication, motor skills and quality-of-life.

The research studies were approved by ethics committees of the respective academic institutions and informed consent obtained from study participants.

Long-term data reveal no safety concerns and indications of clinical benefit and efficacy defined by reduction of seizures, among other neurodevelopmental endpoints specifically meaningful to each individual’s phenotype.