Individualized Antisense Oligonucleotides for SCN2A Related Developmental Epileptic Encephalopathy
Olivia Kim Mcmanus1, Laurence Mignon2, julie douville2, Helen Pu2, Catherine Parisien2, Sarah Glass2, C. Frank Bennett3, Janelle Celso4, Kendall Robbins5, Liana Protopsaltis6, Stephen Kingsmore6, Steven Petrou7, Stan Crooke2, Joseph Gleeson8, Elizabeth Berry-Kravis9
1UC San Diego Rady Children's Institute for Genomic Medicine, 2n-Lorem Foundation, 3Ionis Pharmaceuticals, 4UC San Diego Rady Children's Hospital, 5Rush University, 6Rady Children's Institute for Genomic Medicine, 7The Florey Institute of Neurosciences, 8UC San Diego Rady Children's, n-Lorem Foundation, 9Rush University Medical Center
Objective:
To report long-term efficacy and safety results of individualized antisense oligonucleotide (ASO) therapy for SCN2A-associated developmental epileptic encephalopathy (DEE11) in ongoing n=1 clinical trials.
Background:
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-function (GOF) or mixed function, functionally associated with increased open-probability or greater sodium current flux.
Design/Methods:
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.
Results:
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.
Conclusions:
Open-label investigational individualized ASO therapy demonstrate positive safety and efficacy in patients with different causal GOF and mixed GOF/LOF SCN2A variants and phenotypes, offering new treatment paradigms for more patients with SRD and other monogenic DEEs.
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