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Hopes for Antisense Oligonucleotides Remain Strong Despite Severe Adverse Events in Trials

Two children who were administered an antisense oligonucleotide (ASO) for a severe genetic epilepsy disorder developed hydrocephalus, and one of them died. Experts suggest that while the therapies have potential for these otherwise fatal disorders, they remain highly experimental, and greater efforts should be made to share data from other research and outcomes involving ASOs.

A 3-year-old girl treated with an antisense oligonucleotide (ASO) for a devastating form of genetically caused epileptic encephalopathy died last year after developing hydrocephalus, the principal investigator of the trial reported in October at the annual meeting of the American Neurological Association.

Another child treated with the same ASO also developed hydrocephalus but underwent a successful shunt placement, reported Timothy Yu, MD, PhD, a neurologist, associate professor of pediatrics at Harvard Medical School, and an attending physician in the division of genetics and genomics at Boston Children's Hospital.

Both children had a severe form of KCNT1 epileptic encephalopathy.

“Patients with KCNT1 epileptic encephalopathy can have a range of outcomes, but we specifically selected patients with early infantile migrating focal seizures, who have the absolute worst outcomes,” Dr. Yu said.

“In case series, half of these children die early, with a median age of death of 3 years of age; those that survive continue having dozens of seizures per day and suffer profound neurologic impairment. This severity was critical to our (and our institutional review board's) decision-making in this project.”

Dr. Yu previously revealed that the very first child he treated with an ASO, described in a paper published in 2019 in the New England Journal of Medicine, had also died—not because of an adverse event, but because of her disorder's effects.

The symptoms in all three girls had initially showed significant improvements. Despite the serious adverse events, Dr. Yu told Neurology Today that he remains committed to the study of ASOs for the treatment of neurologic disorders. Other neurologists and neuroscientists said that they, too, continue to have high hopes for ASOs.

“I think the promise is high,” Dr. Yu said. “We were shocked to see the seizures respond as well as they did, especially in patient No. 2 [the one who survived]. And yet we know that we also incurred this serious adverse event in both cases. The intervention has the capability of producing transformative change. We just need more studies. I don't think we will begin to know how successful this approach will be, or not, until we get the numbers up.”

A measure of how promising scientists continue to view ASOs as a means of targeting neurologic disorders can be seen in the recent establishment of several non profit organizations dedicated to their development.

The n-Lorem Foundation seeks to develop and provide ASOs free for so-called nano-rare disorders, those affecting fewer than 30 individuals worldwide. Other newly formed groups include the St. Jude's Center for Experimental Therapeutics, led by J. Paul Taylor, MD, PhD; the Dutch Center for RNA Therapeutics, led by Annemieke Aartsma-Rus, PhD; and the N=1 Collaborative. They seek to not only develop new ASOs but also foster data and share expertise among investigators worldwide.

Still, these serious adverse events have reinforced the view that use of ASOs for nano-rare disorders, when only a handful of children might receive them, places unique burdens on investigators.

“The fact that you can develop an ASO is only one part of the equation,” said Dr. Taylor. “The other part is the appropriateness of treating the patient. Do they have a phenotype that can reasonably expect to benefit from the intervention? Do the parents have realistic expectations? Will insurance cover it? How do we do this in a way that is not haphazard? How do we work cooperatively with people doing similar work? I do worry that this field needs to move forward carefully or we're going to repeat the errors of the gene therapy world.”


We envision a future where individualized medicine centers around the world routinely offer patients customized treatments targeting their condition’s underlying genetic cause.



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