While several therapeutics are available for treating symptoms associated with epilepsy, researchers and patients have strongly called out 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 treat the comorbidities that patients experience. Several biotech companies and researchers are now exploring medical devices and gene therapies to address not just common forms of epilepsy, but also rare conditions such as Dravet Syndrome.
Epilepsy is a highly variable condition, says Thomas Ferraro, PhD, professor at Cooper Medical School of Rowan University’s Department of Biomedical Sciences in Camden, New Jersey. It is associated with different types of seizures, generalised or focal, and specific syndromes that are often rare, like Dravet Syndrome, Lennox-Gastaut Syndrome (LGS), and Rasmussen Syndrome.
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Gene therapies are an attractive way of targeting the underlying genetic mutations, but traditional approaches cannot be used while targeting mutations for Dravet Syndrome, forcing researchers to develop new ways. Meanwhile, others are researching the link between gene variation and different responses to treatments.
At the same time, continuing research into seizures remains key as many available options have side effects and do not benefit all patients. About 30% of epilepsy patients do not respond to available anti-seizure treatments, says Dr. Dario Englot, director of functional neurosurgery at Vanderbilt University’s Institute for Surgery and Engineering in Nashville, Tennessee.
A genetic treatment for epilepsy
Most treatments for epilepsy aim to treat seizures, which is the main symptom of this condition, says Ferraro. 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 in epilepsy research is to modify the disease, says Beth Dean, CEO of CURE Epilepsy, a US-based epilepsy research funder. This is particularly the case for pediatric forms of epilepsy where gene editing techniques like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are becoming more important, says Ferraro.
With the latest advances in whole genome sequencing, it is increasingly clear that rare epilepsies are largely caused by a single genomic mutation, says Ferraro. But while the community already made significant progress in researching the genetics of epilepsy, more needs to be done to understand which mutations cause specific conditions, says Laura S. Lubbers, PhD, chief scientific officer (CSO) of CURE Epilepsy.
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By GlobalDataIn Dravet Syndrome, the approach is to target the SCN1a gene, which has mutations that cause the condition, explains Ferraro. Since this is a rare disease, it is fortunate that the community identified a genetic marker, writes Mary Anne Meskis, executive director of the Dravet Syndrome Foundation. However, targeting SCN1a is a challenge while designing a treatment due to its size, says Carney. Common gene therapies use vehicles such as adeno-associated vectors (AAVs), which cannot carry the required payload in this case, says Carney.
To tackle this, companies have developed different ways to focus on the gene. Stoke Therapeutics is working on an antisense oligonucleotide called STK-001. Rather than replacing mutated genes with functional copies, STK-001 promotes protein production in the healthy copy of the SCN1a gene. This is a smart strategy because the therapy can increase the amount of protein to normal levels, which can restore function, explains Carney, 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.
Nevertheless, such efforts require funding, which remains the biggest challenge facing Dravet Syndrome research, says Meskis. This means that the patient community must drive seed funding for initial research, she adds. Parents and caregivers will continue playing a major role in the field going forwards, 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 screenings can also be used to sharpen the efficacy of already available treatments. In his work, Ferraro focuses on the links between gene variations and different responses to drugs. Even if it’s not a cure, a genomic approach could help with the development of more refined drugs that can target specific pathways, explains Ferraro.
Epilepsy should not be only seen as a condition with seizures, but as one that causes other cognitive deficits, he says. Some patients experience 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 greater certainty over their lives, she adds. Moreover, about a third of epilepsy patients have depression at the time of their diagnosis, she notes. Given these issues, the field needs new anti-seizure drugs that will treat symptoms without worsening comorbidities, says French.
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 linked to a lower-than-expected sudden-death rate.
In November 2019, SK Life Science’s Xcopri (cenobamate) was approved for partial-onset seizures in adults. Since its approval, Xcopri’s use has ramped up in that group of patients, Dr. Vikram Rao, associate professor of clinical neurology at University of California, San Francisco’s Weill Institute for Neurosciences. While Xcopri is a treatment for only the more common epilepsies and not rare monogenetic ones, its approval was described as somewhat of a gamechanger, notes French. SK Life Science is a subsidiary of SK, a South Korean holding company.
There is also an interest in repurposed treatments such as Fintepla for rare diseases, says Carney. 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 in improving the predictability of their condition. Citing an older Epilepsy Foundation poll, French says that patients overwhelmingly say the uncertainty of when they will experience the next seizure is the most difficult aspect of their condition.
Here, medical devices can play a significant role. Based on the latest brain activity research, experts are getting better at predicting the likelihood of future seizures, says Rao. The Spanish startup mjn-neuro sells an earpiece called the mjn-SERAS that records brain activity and warns the user of high seizure risks. In October 2022, mjn-neuro signed a commercialisation agreement with the pharma company Neuraxpharm Group to market mjn-SERAS.
The Epilepsy Foundation has also made headway with its project My Seizure Gauge. The approach combines external devices such as wearables, like a Fitbit and EEG patches, with a seizure diary on a smartphone app, says French. A multi-pronged strategy is needed to manage epilepsy, says Dean. While finding a cure is the eventual target, the community also needs to focus on improving outcomes in the short-term, she adds. New treatments are also needed for pregnant women, states French.
Lubbers echoes this strategy. “There is hope. It is hard on all fronts. It is hard for families. It is hard for researchers. But in my lifetime, I have seen remarkable change and proof that there is hope and change on the horizon.”
Note: This article has been updated to correctly attribute the quotes made by Beth Dean to her. A previous version credited her comments to another Cure Epilepsy representative.
