An antisense oligonucleotide therapy that lowers the amount of Scn8a transcripts — RNA molecules used as a template for the production of proteins — delayed seizure onset and prolonged the lifespan of mice in a model of Dravet syndrome and SCN8A encephalopathy, a study found.
The study, “Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome,” was published in the journal Annals of Neurology.
Dravet syndrome and SCN8A encephalopathy are two severe types of epilepsy that manifest early in life. Both disorders are caused by mutations in genes that provide instructions for making particular sub-units of two different types of sodium channels that are involved in the transmission of electrical signals in the brain.
In the case of Dravet, mutations usually occur in the SCN1A gene, which encodes for a sub-unit of the NaV1.1 sodium channel. In SCN8A encephalopathy, mutations occur in the SCN8A gene, which encodes for a sub-unit of the NaV1.6 sodium channel.
Mutations in the SCN8A gene are known to lead to an overactivation or hyperactivity of the NaV1.6 sodium channel, resulting in seizures that usually fail to respond to anti-epileptic medications, developmental delay, and cognitive impairment at an early age.
Researchers at the University of Michigan School of Medicine, working with investigators at Ionis Pharmaceuticals (which is developing a number of antisense therapies for various diseases), showed that an antisense oligonucleotide therapy that targets and prevents Scn8a transcripts from being used to make a protein can delay the onset of seizures and prolong the lifespan of animals with SCN8A encephalopathy and Dravet.
All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced. DNA is transformed into RNA, which is then transformed to give rise to a protein.
In order to target a specific transcript, or the RNA molecules used as a template for the production of proteins, antisense oligonucleotide therapies use small molecules (antisense oligonucleotides) whose sequence is complementary to the RNA sequence of interest. In this case, researchers chose to target a region of the SCN8a transcript that usually does not harbor mutations.
By doing so, they aimed to reduce the amount of total Scn8a transcripts — both normal and mutated — that were being used to produce a sub-unit of the NaV1.6 sodium channel. Their goal was to lower the channel’s excessive activity in the brain, which is the root cause of seizures.
They then tested these antisense oligonucleotides in a mouse model of SCN8A encephalopathy and Dravet. The small molecules were injected into ventricles in the animals’ brain two days after birth. Some animals received a second injection 30 days after birth. (Ventricles are brain cavities that are filled with fluid.)
In animals with SCN8A encephalopathy, researchers found that treatment led to a dose-dependent reduction of the total amount of Scn8a transcripts. By day 21, the percentage of total transcripts had dropped to approximately 50%, rising back up to normal levels over a period of seven weeks.
They also found that treatment prolonged the lifespan and delayed the onset of seizures in animals with both disorders.
In mice with Dravet, a single dose of antisense oligonucleotide therapy extended their survival from three weeks to more than five months. During this time, the animals showed no signs of seizures, which normally start when animals are 4 weeks old.
Researchers believe these positive effects may be due to the fact that reducing the excitatory activity of the NaV1.6 sodium channel in the brain helps restore the balance of excitatory/inhibitory neural signals that is thought to be the root cause of Dravet.
Excitatory and inhibitory neural signals work as the “yin and yang” of the brain, and are the basis of communication between nerve cells. Excitatory signaling from one nerve cell to the next makes the receiving cell more likely to fire an electrical signal. Inhibitory signaling makes the receiving cell less likely to fire.
“In Dravet syndrome, there is reduced inhibition, and therefore you alter the excitatory/inhibitory balance. We thought that if we bring down the excitatory stimulus by reducing SCN8A, it might compensate for the reduced inhibition,” Miriam Meisler, PhD, a professor of human genetics and neurology at university’s School of Medicine and corresponding author of the study, said in a news story.
In mice with SCN8A encephalopathy, a single injection of antisense oligonucleotides increased their survival for up to seven weeks, and for an additional three weeks in animals receiving a second injection. Treated animals only began to have seizures when they reached 6 weeks old.
In contrast, animals with SCN8A encephalopathy not given antisense oligonucleotide therapy began having severe seizures by day 16 and died within a day.
“This suggests that retreatment could be a long-term solution,” Meisler said. “The next question that arose is whether the treated mice were normal during that extended period.”
To answer this question, researchers recorded treated animals’ brain activity using an electroencephalogram before the onset of seizures, from day 31 to day 39. Findings showed brain activity was normal during this period. Treatment did not lead to weight loss or muscle wasting, and did not affect the animals’ motor function.
“The encouraging news from this study is that treatment significantly extended survival,” said Amy Brooks-Kayal, MD, FAAN, chief and Ponzio Family Chair in Pediatric Neurology and a professor of pediatrics, neurology and pharmacological sciences at the University of Colorado. “That is exciting, because seizures are the likely cause of death in this model.”
This antisense oligonucleotide therapy targeting SCN8A is not the only one of its kind advancing as a form of treatment for severe forms of epilepsy, Brooks-Kayal added. A potential antisense oligonucleotide therapy for Dravet that works to boost the activity of the normal copy of SCN1A — STK-001 by Stoke Therapeutics — is nearing clinical testing.
“I think in the next few years we are likely to see quite a few approvals for ASOs [antisense oligonucleotide therapies],” said Beverly Davidson, PhD, professor of pathology and laboratory medicine and professor of genetics at the University of Pennsylvania Perelman School of Medicine. “They have found a useful niche in neurologic diseases.”
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