Epilepsy, affecting approximately 1.2% of the U.S. population, is a challenging brain disorder characterized by persistent and difficult-to-control seizures, along with cognitive impairments. Though it can often be managed through treatments, it remains incurable. In a promising development, researchers at Emory University have uncovered genetic pathways that offer new insights into combating the seizures associated with this condition.
A multi-institution research team was involved in this investigation, focusing on the chemical pathways that regulate networks of genes in mice. By analyzing these pathways, they aimed to identify patterns of gene activation linked to epileptic seizures. This comprehensive study has implications for improving current treatment methodologies, which typically address only the symptoms of epilepsy.
Nicholas Varvel, an assistant professor in the department of pharmacology and chemical biology at Emory University, has published findings in the journal Science Translational Medicine, highlighting an advance in strategies that can modify the disease itself. “This was one of the first, if not the first, demonstrations of true disease modification,” Varvel stated. “We looked at the spontaneous seizures occurring in these animals, and they were remarkably and enduringly suppressed for up to two months.”
Varvel further explained that various brain conditions, such as head injuries and tumors, can transform a healthy brain into one prone to seizures. The role of inflammatory processes and neuronal death in this transition has been well established, though the specific mechanisms leading to the development of an ‘epileptic brain’ have remained unclear.
To delve deeper, the research team examined over 6,000 active genes in mice experiencing epilepsy, utilizing a custom algorithm named MAGIC (Mining Algorithm for Genetic Controllers) to analyze the transcriptional signaling pathways associated with the condition.
“Our goal was mass data mining to determine which signaling mechanisms are activated following an initial seizure,” Varvel remarked, emphasizing the importance of understanding these genetic controls in relation to epilepsy.
Among their findings, the researchers discovered specific gene clusters that were repressed after epileptic events, while others exhibited increased expression levels. Notably, one genetic signaling pathway was activated following an initial seizure and then re-engaged during a later stage when epilepsy was established, suggesting a complex, two-fold engagement in these processes.
With a clearer understanding of these genetic pathways, the researchers turned their attention to tofacitinib, an existing medication known to inhibit the JAK/STAT activation process, initially developed for treating rheumatoid arthritis. Upon administering the drug to the epileptic mice, the researchers observed that the initial wave of seizures persisted; however, targeting the subsequent wave of seizures revealed striking results: a reduction in seizure severity and frequency of up to 80%. Remarkably, eight out of ten mice were found to be seizure-free a month after ceasing the drug.
In addition, cognitive improvements were also noted among the treated mice, illustrating potential benefits beyond merely controlling seizures. Varvel highlighted that these outcomes were markedly different from traditional epilepsy medications, which typically focus only on alleviating symptoms.
“Our experimental design allowed us to demonstrate that even after removing the drug for as long as two months for seizures and up to two weeks for behavioral impairments, the animals remained free of the disease,” Varvel noted, showcasing the long-lasting impact of their approach.
To ensure the validity of their findings, the research team replicated their experiments in various laboratories nationwide, achieving consistent results. Although the precise biochemical mechanisms at play remain to be fully elucidated, the team is committed to further investigations to clarify how tofacitinib blocks seizures at the cellular level.
Looking ahead, Varvel believes that tofacitinib may have an advantageous path toward clinical application in humans, given that it has already been approved for rheumatoid arthritis. Before initiating clinical trials, however, he intends to conduct a retrospective epidemiological study focusing on individuals already using tofacitinib to assess any correlation with reduced epilepsy incidence.
“This is a drug that has been on the market for many years,” he remarked. “We can explore the incidence of epilepsy among those taking tofacitinib for rheumatoid arthritis. The goal is to determine if this population experiences significantly lower epilepsy rates compared to the general public.”
A positive outcome from this investigation could pave the way for clinical trials involving individuals with epilepsy who do not respond to existing treatments.
“Whenever there is an already FDA-approved drug, it simplifies the journey toward human trials,” Varvel pointed out. “Considering that one-third of people with epilepsy do not respond to current medications, the next step would be to initiate a clinical trial for those individuals unable to benefit from available options.”
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