Children with a rare and difficult-to-control form of epilepsy called Dravet syndrome have new hope thanks to landmark research data showing the effectiveness of an RNA-based medicine, STK-001, to improve seizure control and modify disease progression.

The breakthrough was announced in March by Stoke Therapeutics, Inc., the company testing the use of STK-001. Data from a trial called MONARCH and study called SWALLOWTAIL showed that children and adolescents 2 to 18 years of age with Dravet syndrome who were treated with the medicine experienced a reduction in the number of convulsive seizures. They also showed improvement in other conditions that commonly result from Dravet syndrome such as developmental delays, speech and language problems, and balance and walking issues.

Four children with Dravet syndrome treated at Cook Children's Jane and John Justin Institute for Mind Health participated in one or more of the trials. M. Scott Perry, M.D., epileptologist and head of the Justin Institute, is the lead investigator for the SWALLOWTAIL trial.

The MONARCH trial studied the safety and effectiveness of the medicine. Following the completion of MONARCH, qualifying patients could also join the SWALLOWTAIL trial studying the long-term safety and tolerability of repeat doses of the drug. The SWALLOWTAIL study is ongoing.

“What the data tells us is that this medicine has the potential to be disease-modifying, meaning it changes the course of the disease over just treating the seizures,” Dr. Perry said. “In the world of epilepsy, the treatments we have are primarily symptom-treating. We treat the seizures, which are a symptom of the epilepsy, but we don't necessarily correct the underlying problem unless we’re talking about a lesion on the brain that can be surgically removed. Dravet syndrome is caused by a mutation in the SCN1A gene, so this treatment works on the gene itself to correct the problem and improve some of the comorbid conditions.” 

Understanding Dravet Syndrome

Genes are segments of DNA that contain instructions for building proteins, which are essential for the structure and function of the body. Because humans inherit two copies of most genes, one from each parent, individuals with Dravet syndrome typically have one normal copy and one mutated copy of SCN1A. This gene provides instructions for making a sodium channel protein that is critical for the normal function of brain cells. Mutations in one copy of the gene can lead to the production of defective sodium channels, which disrupt the electrical activity of neurons and contribute to seizures and other Dravet syndrome symptoms.

Our DNA produces a molecule called messenger RNA (mRNA). It acts as the intermediary between DNA and protein synthesis by carrying genetic information from DNA to the protein-making machinery within a cell. It also plays a role in the regulation of protein production and will sometimes instruct the body to discard copies of genes, even if those genes are healthy. In this case, copies of the SCN1A gene.

The STK-001 medicine works by introducing a synthetic material called antisense oligonucleotide (ASO) that binds to mRNA and stops it from discarding gene copies, whether they're good or bad. By keeping all healthy gene copies from one SCN1A gene, more functional proteins are produced, essentially making up the loss caused by dysfunctional copies of the gene.

“So all of the mutated copies get made and all of the healthy copies get made, and it's okay that the mutated copies get made because they don't work,” Dr. Perry said. “By keeping all of the healthy copies, we effectively can replace the 50% that were non-functional from the mutated gene by making everything from the healthy version.”

While ASO technology has been used for many years to treat other genetic disorders, like spinal muscular atrophy, this is the first treatment of its kind for epilepsy.

“It's a big deal to have a precision medicine therapy meant to treat the underlying problem,” Dr. Perry said. “If you do this kind of treatment early on in life before a child starts to have developmental delays, you might be able to prevent some of the significant developmental and behavioral problems typical in Dravet syndrome patients. It's harder to reverse things once a child is already behind, but imagine if we could do this early on and avoid getting behind to begin with.”

Team Approach

Participation in these trials requires collaboration between multiple specialties, which is something the Justin Institute for Mind Health is uniquely designed for. The Institute connects nine specialties that treat the mind and nervous system under one roof, including Neuropsychology, which performs the cognitive developmental testing required for the trial. Administration of STK-001 also requires support from the Anesthesia department as the drug is given every four months via a spinal tap while often under sedation.

STK-001 has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and rare pediatric disease designation by the FDA as a potential new treatment for Dravet syndrome, according to Stoke Therapeutics, Inc.

Dr. Perry expects that this type of ASO therapy will be replicated for other genetic epilepsies and gene mutations in the future.