Mutation-Tailored Antisense Drugs Reduce Seizures in Two Boys With Severe Epilepsy

For patients with rare genetic diseases, identifying the disease-causing mutation is often merely the endpoint of diagnosis and does not necessarily mean that a treatment is available. Now, researchers have separately designed antisense oligonucleotides (ASOs) that target only the disease-causing version of the gene in two boys with severe developmental and epileptic encephalopathy. After treatment, both experienced fewer seizures and gradually acquired new language and motor skills.

These two parallel single-patient trials enrolled a 9-year-old boy and a 14-year-old boy, both of whom carried disease-causing SCN2A mutations. SCN2A produces an important component of neuronal sodium channels, and certain mutations cause abnormal neural signaling, leading to drug-resistant epilepsy, developmental delay, and impairment across multiple areas of functioning. The results showed that seizure frequency fell by 26% in one patient and by 90% in the other, while both also reduced some of their concomitant medications.

The ingenuity of the treatment lies in the fact that the researchers did not directly target each disease-causing mutation. Instead, they targeted a benign intronic variant located on the same chromosome as the disease-causing version. The team created a different ASO for each patient to identify and reduce SCN2A transcripts carrying the mutation while preserving as much as possible the function of the other, healthy copy of the gene. This approach modulates gene expression without permanently rewriting DNA, so continued dosing is required.

The drugs were injected into the spinal fluid under anesthesia approximately once every two to three months. At age 15, the older patient was able to walk independently for the first time. The research team also observed that his abilities declined before the next dose, prompting the US Food and Drug Administration to approve an adjustment to the dosing frequency. In addition to motor improvements, both patients improved in language, sensory processing, and adaptive behavior, and the older patient also required fewer medications to treat chronic gastrointestinal problems.

At the time the results were published, both patients had received treatment for more than two years. The researchers reported no ASO-related adverse events or serious adverse events, and laboratory tests, electrocardiograms, and electroencephalograms also remained stable. However, two cases cannot answer questions about rare but serious side effects, long-term neurodevelopmental trajectories, or the optimal dose. Functional changes beyond seizure improvement may also have been influenced by rehabilitation, age, and other treatments and must be interpreted cautiously.

Another challenge for personalized medicines is scale: if each molecule can serve only one patient, the costs of development, manufacturing, and regulation are difficult to accommodate within traditional models. The researchers further examined genetic data from 19 patients and found that 3 had compatible genetic configurations, suggesting that the same ASO might be usable for a small group of patients. This finding is not yet sufficient to demonstrate general efficacy, but it offers a testable path—using a patient-specific genetic marker to avoid the healthy copy of the gene, potentially giving even ultra-rare diseases an opportunity for precision intervention.