Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications (ASMs) can control seizures in two thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one third, as does the lack of disease-modifying therapies.
But RNA-based therapeutics offer new hope and experts predict they could fill these gaps and revolutionize epilepsy treatment.
“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,'” David Henshall, PhD, Royal College of Surgeons Ireland (RCSI), Dublin, told Medscape Medical News.
Edward Kaye, MD, pediatric neurologist and CEO of Stoke Therapeutics agrees. “RNA therapeutics open up possibilities that we could not have been imagined when I started my career,” he said in an interview.
“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” Kaye told Medscape Medical News.
Thank COVID?
Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, note that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.
Klitgaard and Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published in Epilepsia online on September 13, 2023.
Unlike current ASMs, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.
RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.
Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.
“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” Klitgaard told Medscape Medical News.
“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure suggesting significant disease-modifying properties with a curative potential for epilepsy.”
Hope for Dravet Syndrome
Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.
Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.
The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.
“These new data suggest clinical benefit for patients 2 to 18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.
Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.
“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Kaye commented.
“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Kaye.
“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis and the time has come for genetic epilepsies,” he added.
A Promising Future
Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”
And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.
Take, for example, a case reported recently in The New England Journal of Medicine.
Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease.
Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.
One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.
However, Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”
“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Kauppinen said.
The review article on RNA therapies in epilepsy had no commercial funding. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from N EUmiRNA Therapeutics. Klitgaard and Kauppinen are cofounders of NEUmiRNA Therapeutics. Kaye is CEO of Stoke Therapeutics.
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