Precision medicine for epilepsies: are we there yet?

Abstract

Precision medicine (PM) aims to offer a therapy targeted to the molecular abnormality that leads to the specific phenotype. Monogenic epilepsies naturally lend themselves to PM approach. But are we there yet? The study by Ballestrini et al surveyed six tertiary epilepsy centres to understand the ‘reallife’ complexities of PM. Out of 293 patients with various forms of genetic epilepsies, an established PM treatment was available for 19% of them. However, only 30% of patients receiving PM treatments had a meaningful decrease in seizure frequency. Interestingly, the genetic diagnostic also prompted further diagnostic assessment (for instance, cardiologic investigation) and changes in antiseizure medications (ASMs) in 35%. Overall, improvement in quality of life as a result of changes following the molecular diagnosis were observed in 39% of patients. PM therapies available today are mainly focused on monogenic developmental and encephalopathic epilepsies. These are very severe epilepsies often associated with intellectual disability, motor problems and higher mortality rates than other more common forms of epilepsy. Therefore, even though one would like to see a much greater rate of improvement with PM, the findings of Balestrini et al are encouraging. Specially as they reflect the reality of patients that had several years of enduring seizures that could not be controlled with most available ASM, surgical (resective, disconnection, neuromodulation) and dietary therapies. Importantly, in the Ballestrini et al study, the PM changes observed after a genetic diagnosis were changes in ASM, dietary approaches, use of supplements or repurposed drugs. These changes help minimise the damage caused by the different genetic defects, but do not provide a direct replacement of the damaged or absent protein. Another form of PM, which was not evaluated in the Ballestrini et al study, is through a direct attempt at replacing the abnormal or missing protein. One example of that is cerliponase alfa, a recombinant form of human tripeptidyl peptidase-1 (TPP1), which received FDA approval in 2017. Biallelic CLN2 variants lead to a decrease in TPP1 and a fatal form of progressive myoclonus epilepsy. However, cerliponase alfa is only approved for children 3 years or older, which may not be enough to revert the first 3 years of accumulation of lysosomal storage material in cells. Other forms of replacing abnormal proteins through gene therapy and antisense oligonucleotide treatments are being developed for other forms of epilepsy. At least in animal studies, these are very promising PM approaches, which address not only the seizures but also other comorbidities and mortality. The first human trials are underway for some of these conditions. Several challenges are still in the way of PM: how to treat polygenic epilepsies? Should we offer neonatal screening of conditions for which we have a PM approach ? At what age should PM be started, before or after symptom onset? What measures should be evaluated when determining the efficacy of PM: seizure count, motor, intellectual and psychiatric comorbidities, mortality rates? Who will pay for these treatments? Despite the challenges ahead, the present time shows that PM is already possible for a few forms of epilepsy and the future will bring a new reality where seizures and comorbidities burden will be significant reduced or even eliminated—at least for some forms of epilepsy.