Credit: Shutterstock/SewCream
While multiple therapeutics are available to treat symptoms associated with epilepsy, researchers and patients have strongly emphasized the need for more holistic treatments that would address the condition as a whole. Although recently approved drugs can treat seizures more safely, they do not address the comorbidities patients suffer from. Several biotech companies and researchers are currently exploring medical devices and gene therapies to treat not only common forms of epilepsy but also rare diseases like Dravet syndrome.
Epilepsy is a highly variable condition, says Thomas Ferraro, PhD, a professor at Cooper Medical School in the Department of Biomedical Sciences at Rowan University in Camden, New Jersey. It is associated with different types of generalized or partial seizures and specific, often rare, syndromes such as Dravet syndrome, Lennox-Gastaut syndrome (LGS) and Rasmussen syndrome.
Gene therapies are an attractive way to target the underlying genetic mutations, but conventional approaches cannot be used when targeting mutations for Dravet syndrome, forcing researchers to develop new avenues. Meanwhile, others are exploring the link between gene variations and differential responses to treatments.
At the same time, continued research into seizures remains crucial, as many available options have side effects and do not benefit all patients. About 30% of people with epilepsy don’t respond to available anti-seizure treatments, says Dr. Dario Englot, director of functional neurosurgery at the Department of Surgery and Engineering at Vanderbilt University in Nashville, Tennessee.
A genetic treatment for epilepsy
Most treatments for epilepsy aim to treat seizures, which are the main symptom of this condition, Ferraro says. However, these are preventive treatments rather than cures, says Dr. Paul Carney, Director of Child Neurology and Epilepsy at the University of Missouri, Columbia. But now the goal of epilepsy research is to modify the disease, says Beth Dean, CEO of CURE Epilepsy, a US-based funder of epilepsy research. This is especially true in pediatric forms of epilepsy, where gene editing techniques such as clustered regularly interspaced short palindromic repeats (CRISPR) are becoming increasingly important, Ferraro says.
With recent advances in whole-genome sequencing, it’s becoming increasingly clear that rare epilepsies are largely caused by a single genomic mutation, Ferraro says. But while the community has already made significant strides in understanding epilepsy genetics, more needs to be done to understand which mutations cause certain disorders, says Laura S. Lubbers, PhD, CURE Epilepsy’s chief scientific officer (CSO).
In Dravet syndrome, the approach is to target the SCN1a gene, which has mutations that cause the condition, Ferraro explains. Because the disease is rare, it’s fortunate that the community has identified a genetic marker, writes Mary Anne Meskis, executive director of the Dravet Syndrome Foundation. But targeting SCN1a is a challenge in developing a treatment because of its size, says Carney. Traditional gene therapies use vehicles like adeno-associated vectors (AAVs), which in this case can’t carry the required payload, says Carney.
To counteract this, companies have devised various ways to target the gene. Stoke Therapeutics is working on an antisense oligonucleotide called STK-001. Instead of replacing mutated genes with functional copies, STK-001 promotes protein production in the healthy copy of the SCN1a gene. It’s a smart strategy because therapy can increase protein levels to normal levels, which can restore function, Carney explains, adding that in Dravet, one copy of the SCN1a gene is functional while the other has a mutation. Other approaches include Encoded Therapeutics’ early-stage therapy ETX101, which also works by increasing SCN1a expression.
Still, such efforts require funding, which remains the biggest challenge for research into Dravet syndrome, Meskis says. This means the patient community must drive seed funding for the initial research, she adds. Parents and carers will continue to play an important role in this area, says Dr. M. Scott Perry, director of the Genetic Epilepsy Clinic at the Jane and John Justin Institute for Mind Health at Cook Children’s in Fort Worth, Texas.
New developments in the anti-seizure pipeline
Genomic screens can also be used to hone the effectiveness of already available treatments. Ferraro’s work focuses on the connections between gene variations and different responses to drugs. While it’s not a cure, a genomic approach could help design more sophisticated drugs that can target specific signaling pathways, Ferraro explains.
Epilepsy shouldn’t just be seen as a condition with seizures, but one that causes other cognitive deficits, he says. Some patients suffer from cognitive dysfunction and comorbidities that affect their memory and mood, says Dr. Jacqueline French, Chief Medical Officer (CMO) of the US-based Epilepsy Foundation. Research into devices is also important as it would give patients more security about their lives, she adds. In addition, about a third of epilepsy patients have depression at the time of their diagnosis, she notes. Faced with these issues, the field needs new anti-seizure drugs that treat symptoms without exacerbating comorbidities, French says.
Some newly approved drugs have improved the situation. UCB’s Fintepla (fenfluramine), an anti-seizure drug for Dravet and Lennox-Gastaut syndrome, is a recently approved treatment that has been associated with a lower than expected rate of sudden death.
In November 2019, SK Life Science approved Xcopri (cenobamate) for partial-onset seizures in adults. Since its approval, the use of Xcopri in this patient population has increased significantly, said Dr. Vikram Rao, associate professor of clinical neurology at the Weill Institute for Neurosciences at the University of California, San Francisco. While Xcopri is only a treatment for the more common epilepsies and not the rarer monogenetic ones, its approval has been described as something of a game changer, notes French. SK Life Science is a subsidiary of SK, a South Korean holding company.
There’s also interest in repurposed treatments like Fintepla for rare diseases, Carney says. GW Pharmaceuticals’ Epidiolex (cannabidiol), the first FDA-approved CBD treatment, is also a valuable addition, he adds. Epidiolex is approved for Dravet syndrome, LGS and tuberous sclerosis complex.
A multi-pronged approach
Although new treatments are important, a key area of interest for patients remains improving the predictability of their condition. Citing a previous survey by the Epilepsy Foundation, French says patients overwhelmingly say that not knowing when they will have their next seizure is the most difficult aspect of their condition.
Medical devices can play an important role here. Based on the latest brain activity research, experts are getting better and better at predicting the likelihood of future seizures, says Rao. Spanish startup mjn-neuro sells a handset called mjn-SERAS that records brain activity and warns the user of high risk of seizures. In October 2022, mjn-neuro signed a commercialization agreement with pharmaceutical company Neuraxpharm Group to commercialize mjn-SERAS.
The Epilepsy Foundation has also made progress with its My Seizure Gauge project. The approach combines external devices like wearables like Fitbit and EEG patches with a seizure diary in a smartphone app, says French. A multi-pronged strategy is needed to treat epilepsy, says Dean. While finding a cure is the ultimate goal, the community must also focus on improving outcomes in the short term, she adds. New treatments are also needed for pregnant women, says French.
Lubbers repeats this strategy. “There is hope. It’s tough on all fronts. Families have a hard time. Researchers have a hard time. But in my life I have seen remarkable changes and evidence that there is hope and change on the horizon.”
Note: This article has been updated to correctly attribute Beth Dean quotes to her. An earlier version attributed their comments to another Cure Epilepsy representative.
