Abstracts

SCN2A-associated developmental epileptic encephalopathy 11 (DEE11) is a rare disease with no approved treatments. The two patients described have nano-rare causal SCN2A variants precluding their participation in ongoing commercial clinical trials. The n-Lorem Foundation is a non-profit organization dedicated to the discovery, development, and manufacturing of individualized antisense oligonucleotides (ASOs) for free, for life, for nano-rare patients. We have created two individualized ASOs specifically targeted to each patient’s pathogenic variant with the aim of slowing disease progression by alleviating symptoms and improving quality of life. Herein, we present how each patient’s trial was customized to their specific phenotypic impairments with outcomes measures assessing seizures, behavior, communication, and motor skills. We will present preliminary clinical efficacy and safety findings in both clinical trials and discuss the unique challenges encountered in each specific program.

The FDA approved both clinical trials under the 2021 guidance for Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases. Investigational intrathecal dosing is ongoing for both patients under their respective approved research INDs. The first patient (nL00333) is a 10-year-old male with a pathogenic, dominant gain-of-function variant in the SCN2A gene (c.5645 G >A, p.Arg1882Gln). The main study outcome measures for this patient include frequency of treatment-resistant seizures, changes in adaptive behavior, sensory sensitivity, cognition and language as well as behavioral irritability. This patient has received 7 intrathecal doses of ASO over approximately 14 months with an unremarkable safety and tolerability profile. The second patient (nL00001) is a 15-year-old male with a pathogenic, mixed gain/loss of function variant in the SCN2A gene (c.2558G >A, p.Arg853Gln) and for whom study outcome measures include frequency of treatment-resistant seizures, changes in autonomic and gastrointestinal symptoms, and changes in neurodevelopment including motor function.  This patient has received 4 intrathecal doses of ASO over approximately 5 months with no safety or tolerability concerns.

Early data show preliminary indications of clinical benefit as defined by periods of substantial reduction of seizures, among other endpoints specifically meaningful to each individual’s phenotype.

In combination with rapid genome sequencing, which allows genetic diagnosis of DEE11 within days of first-time seizure, targeted therapies have the potential to not only decrease seizures but also impact neurodevelopment.  This work further demonstrates the efficiency, versatility, and specificity of ASO technology as an important enabling platform technology in the development of safe and effective individualized therapies, offering new potential targeted therapies for nano-rare patients with this and other developmental epileptic encephalopathies.

This research is supported in part by California Institute for Regenerative Medicine (CIRM).