Two children who have had to endure seizures for most of their lives are now seeing significant improvement thanks to a personalized genetic medicine treatment. The 9-year-old and 14-year-old were both diagnosed with SCN2A-related developmental epileptic encephalopathy, a rare form of childhood epilepsy, from a young age.
The genetic mutation that causes the condition, a new study published in Nature Medicine shows, can effectively be suppressed with short, synthetic pieces of DNA that are designed to degrade the mutant copy of the SCN2A gene that promotes epilepsy. Following clinical trials involving this personalized gene therapy, the two children have seen major health improvements. The treatment has even helped the 14-year-old patient walk independently for the first time in his life.
“We’ve seen changes across the board, showing that targeting the root genetic cause can produce measurable improvement,” said study author Kim‑McManus, an associate professor of neurosciences at the University of California San Diego School of Medicine, in a statement.
A Rare Form of Epilepsy
Developmental and epileptic encephalopathies (DEEs) are a group of rare and severe epilepsies that often begin in infancy or childhood, according to the Epilepsy Foundation.
Although they’re mainly associated with frequent seizures, they can also prompt additional conditions like movement disorders, intellectual disabilities, and gastrointestinal problems. The “encephalopathy” aspect of DEEs refers to the fact that they disrupt normal brain function and development, leading to developmental delay in children.
The 9-year-old patient treated in the study had a history of seizures, along with a severe intellectual disability and autism spectrum disorder. The 14-year-old patient had a history of multiple seizure types, a severe neurodevelopmental delay, and erratic muscle movements that left him unable to walk independently.
Neither child used spoken language and communicated with assistive communication boards.
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Mutations of the Gene
Many DEE cases arise from genetic causes — the condition of the two children, for instance, resulted from mutations of the sodium voltage-gated channel alpha subunit (SCN2A), a gene that encodes instructions to make a protein called a sodium channel.
Mutations of this gene, according to the Children’s Hospital of Philadelphia, can impair the flow of sodium ions in the brain in different ways; in some cases, a mutation may lead to overactivity of the ion channel, while in other cases, it leads to decreased activity of the ion channel. In most cases, the mutated variant occurs spontaneously and is not inherited from either parent.
Since traditional anti-seizure medications are often ineffective at treating this condition, researchers turned to a personalized gene therapy, hoping it could address the root problem of SCN2A single mutations in both children, which affected only one of their gene’s two copies. Over a two-year period, the two children were injected regularly with synthetic DNA segments called allele-selective antisense oligonucleotides (ASOs), which could recognize harmless regions of DNA located next to each child’s mutation.
The ASOs were injected under anesthesia directly into spinal fluid every two to three months, essentially silencing the mutant version of SCN2A while leaving the other copy unscathed.
The Promise of Personalized Gene Therapy
After two years, the researchers noticed multiple improvements in both children. The 9-year-old, who had seizures nearly every day, experienced a 26 percent drop in seizure frequency. The 14-year-old experienced a 90 percent reduction in seizure frequency and fewer gastrointestinal issues.
Both children also saw improvements in language and motor skills, sensory processing, and adaptive behaviors. The 14-year-old could walk independently for the first time, and has continued showing progress after the researchers adjusted his doses.
“Since then, he's been walking independently,” said Kim-McManus. “When we really think about precision therapy in a personalized way, you can't get more personalized than that.”
Lastly, the children experienced no serious side effects from the trials. Their gradual improvement has shown how personalized gene therapies can help multiple people with severe conditions, not just single, isolated cases. Some day, these therapies may even work as successful treatments for a multitude of different neurological and non-neurological diseases caused by single mutations.
“It’s like a sci-fi, Star Trek idea, and that's the look that I used to get when I was just starting this,” said Kim-McManus. “But now that we're on the other side showing safety and efficacy, the idea is spreading beyond academia to the pharma and biotech industry and having a big impact.”
This article is not offering medical advice and should be used for informational purposes only.
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