Allele-Selective ASO Therapy Enables Teen with Rare SCN2A Epilepsy to Walk for the First Time
核心洞察
An investigational antisense oligonucleotide (ASO) (搜索) reduced seizures by 90% in a 17-year-old with SCN2A-related developmental and epileptic encephalopathy (搜索), a rare genetic disorder.
Connor Dalby, who had never walked unassisted in his life, began taking independent steps approximately four months after his first intrathecal dose at age 14.
The allele-selective approach, published in *Nature Medicine*, knocks down the mutated SCN2A (搜索) gene while sparing the healthy copy, a strategy that may generalize to many patients.
For the first 14 years of his life, Connor Dalby could not walk. Afflicted by hundreds of seizures daily since infancy, he spent much of his childhood in hospitals, on feeding tubes, and cycling through more than a dozen anti-seizure medications that offered little relief. Today, at 17, he can take 50 to 60 steps on his own — a transformation his mother, Kelley Del Real, calls nothing short of miraculous. The catalyst: an experimental, allele-selective antisense oligonucleotide (ASO) (搜索) designed specifically for his rare genetic mutation, delivered directly into his spinal fluid.
The results of this n-of-1 clinical effort, led by Dr. Olivia Kim-McManus of UC San Diego and Rady Children's Hospital, were published last week in the journal Nature Medicine. The work was conducted in collaboration with the n-Lorem Foundation, a nonprofit founded by Ionis Pharmaceuticals (搜索) founder Stan Crooke to develop personalized medicines for patients with ultra-rare genetic conditions, and Ionis Pharmaceuticals in Carlsbad.
A devastating diagnosis and a relentless search
Connor was diagnosed around age 4 with SCN2A-related developmental and epileptic encephalopathy (搜索) (DEE), a rare disorder caused by a random mutation in one of his SCN2A (搜索) genes. The condition belongs to a group of disorders in which abnormal brain activity not only triggers seizures but also disrupts development, movement, communication, and daily functioning.
"It was around the clock. So 50 to 100 seizures a day, all day, all night," Del Real recalled. At age 2, the seizure burden was so severe that Connor was temporarily placed on hospice status. "He did nothing but sort of lie on his back on a feeding tube. He didn't smile anymore, there was no laugh."
Del Real, a former high school English teacher with no scientific background, immersed herself in genetics research. She co-founded RogCon Biosciences (搜索), which later licensed a therapeutic candidate targeting gain-of-function SCN2A (搜索) mutations to Praxis Precision Medicines. That drug is now in phase 3 clinical trials. However, Connor's particular mutation did not fit the profile for that therapy.
An allele-selective strategy
Connor's mutation is especially complex. "He carries a more complex variant that requires an allele-selective approach because he has both seizures and autism," said Kim-McManus, a child neurologist and director of Rady's Precision Therapeutics Neuro-Interventional Program.
The therapeutic strategy exploits a fundamental genetic fact: children inherit one copy of each gene from each parent. Connor's disease-causing SCN2A (搜索) gene drives neuronal over-excitation, producing seizures. His other copy functions normally. The ASO was designed to selectively knock down signals from the mutated gene while sparing the healthy copy.
Crucially, the benign genetic differences that allow this discrimination are not infinitely variable across the population. This means the approach could potentially be applied to patients with a range of harmful SCN2A (搜索) mutations rather than requiring a bespoke drug for every individual. "We have already identified numbers of patients that could potentially benefit from sequencing infants," Kim-McManus said. "There's a massive potential impact here."
Dr. Timothy Yu, a neurologist at Boston Children's Hospital and assistant professor at Harvard University, called the selective knockout approach "elegant." He noted that similar strategies had been attempted — unsuccessfully — in Huntington's disease and in 2023 for a patient with the neurological disorder KIF1A. "These benign differences, if they're found in, let's say, 25% of us, it turns out that those are sweet spots because then you have the opportunity for kids to have one good copy, and there is a difference that you can exploit," Yu said. "It means you don't necessarily have to make a different drug for every single patient; you've got just enough commonality that you can wedge in a drug to discriminate between the good copy and the bad copy."
Clinical outcomes: beyond seizure reduction
Connor received his first intrathecal dose at age 14 under a protocol reviewed and approved by the FDA's Investigational New Drug program. About four months later, he began attempting unassisted steps for the first time in his life.
The drug reduced his seizures by approximately 90%. But the benefits extended far beyond seizure control. Del Real reports that Connor is calmer overall, his sleep has dramatically improved — from waking for hours in the middle of the night to sleeping from about 9:30 p.m. to 4:30 a.m. — and he has gained the ability to use his hands in ways previously impossible. Some behavioral improvements, such as the elimination of screaming episodes when vehicles slowed down, have persisted even during the washout periods between doses.
The treatment is not without limitations. The effects wear off one to two weeks before each subsequent dose, and it takes another week or two after dosing for full effect to return. "We get a solid five, six weeks where he's doing really well with everything," Del Real said. Connor remains on the severe end of the autism spectrum, cannot speak, and still often requires caregiver guidance while walking.
Yet the gains are undeniable. "I got to take him on his first roller coaster. It was the best moment ever," Del Real said. "Just something that we never thought he would be able to handle."
A glimpse of precision medicine's future
Kim-McManus acknowledged that bringing personalized genetic medicines to more patients will require sustained research and funding. But Connor's case offers a powerful proof of concept. "It's hard to deny what we were seeing at the beginning," she said. "So that was very exciting and hopeful."
Yu agreed that the walking milestone is extraordinary. "That's highly, highly unusual," he said. "I'd really, really say it's something worth celebrating."
Del Real, who now works at Praxis Precision Medicines, tells her son how many families and children he is helping. "He was the first human ever to be treated with this molecule," she said. The hope is that what researchers learned from treating one child could eventually help many more — and that detecting such mutations shortly after birth and intervening early could help children avoid the developmental delays caused by years of uncontrolled seizures.
Funding for the trial came from the California Institute for Regenerative Medicine.