Editorial Cite This: ACS Chem. Neurosci. 2019, 10, 2080−2081
pubs.acs.org/chemneuro
Precision Medicine in EpilepsyThe Way Forward? hat do you think of when you hear the term “precision medicine”? The National Institutes of Health definition is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.″ The most frequently cited examples of precision medicine come from the field of oncology, where genomic sequencing of tumors can give us a way of targeting individual somatic changes. Indeed, if you search PubMed for “precision medicine oncology”, you get over 120 000 hits; search “precision medicine epilepsy”, and you get 270. The reason for the lower number of hits is that the field of epilepsy therapeutics, like that of many other neurological disorders, has traditionally been dominated by the search for downstream pathways that (in the case of epilepsy) could be targeted effectively to end seizures, irrespective of the initial cause. However, the landscape of epilepsy genetics has changed dramatically over the last few decades, as illustrated so clearly by Helbig et al..1 Until 10 years ago, the only genes directly implicated in epilepsy were those encoding ion channels, where causative mutations were found in large pedigrees. More recently, the use of exome sequencing has led to an explosion in the number of epilepsy genes, largely identified via the use of “trios” in which the exomes of both parents and an affected child are sequenced, enabling de novo mutations to be detected. This strategy has been particularly successful in early onset severe epilepsy; these cases are purely genetic, but would appear to be sporadic at a population level. So how do we get from genetics to therapy? In some cases, once the mutation has been identified, there is enough known about the underlying biochemistry to suggest an immediate therapeutic strategy. There are some striking examples of this approach. One early example, that in fact predates exome sequencing, is the treatment of children with mutations in the SLC2A1 gene that result in glucose transporter type 1 deficiency. These children typically develop epilepsy within the first year of life, often associated with other neurodevelopmental problems. Early treatment of affected children with a ketogenic diet, which provides ketone bodies as an alternative energy source for the brain (bypassing the need for glucose transport) can provide not only relief from seizures but also prevention of intellectual disability. Similarly, individuals with mutations in ALDH7A1 can achieve good control of seizures with a relatively straightforward treatment consisting of high doses of pyridoxine. For newly identified genes that have emerged from exome sequencing, it is too early to know what novel precision therapies will emerge. However, what is becoming clear is that knowing not just the identity of the gene, but the precise nature of the mutation, can be critically important in determining the correct treatment. A recent example of this was seen in the case of individuals with mutations in the SCN2A gene that encodes the voltage-gated sodium channel Nav1.2. A wide range of neurological phenotypes are seen with mutations in this gene, from late onset epilepsy to epileptic
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encephalopathies with a neonatal onset. Truncating mutations, presumably loss of function, were found to be associated with late onset, milder phenotypes. Individuals with these mutations showed no therapeutic response to sodium channel blockers; indeed, in some cases their condition even worsened. In contrast, most early onset severe cases were found to have missense mutations in SCN2A that conferred a gain of function, and treatment of these children with sodium channel blockers was associated with a good response.2 Clearly, a detailed understanding of the nature and functional consequences of the precise mutation, and not just knowing which gene is mutated, will be crucial to determine the correct treatment protocols in cases like this. It is only too easy to imagine a scenario in which a clinical trial fails because all patients with mutations in a given gene have been lumped together. In fact a recent publication appears to provide a stark illustration of this.3 Mutations in KCNT1 can cause either an inherited form of epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), or they can result in early onset epileptic encephalopathy. Treatment of the latter form with quinidine, a channel blocker, has shown variable but sometimes dramatic apparent efficacy in open label studies. However, a randomized trial of the very same drug in ADNFLE patients showed not only that administration of quinidine was associated with the development of cardiac irregularities, but that the drug had no effects on either the frequency or severity of seizures in this group. How can we reconcile this apparent need for a detailed understanding of the underlying mutation in every single individual, on the one hand, with the most commonly used strategies for discovering novel antiepileptics (like those we often report in ACS Chemical Neuroscience), on the other?4−6 In the future, we will likely see increasing numbers of papers on drugs that target the functional consequences of mutations in specific genes, but the use of precision medicine in every single individual would be a Herculean task given the numbers of genes being identified. Perhaps the way forward will be a merging of precision medicine approaches with those of other studies that combine both rare genetic causes, mutations in the same genes in much milder cases of epilepsy, and changes in gene expression in common epilepsies. Delahaye-Duriez et al. provide a great example of this approach, using a systems-level approach to identify a network of 320 coexpressed genes enriched for both rare and common epilepsy-causing mutations.7 This gene network was consistently downregulated in samples of epileptic brain tissue from both humans and mice. The authors went on to identify a number of existing antiepileptic drugs that were predicted to upregulate genes across the network. A wider application of this approach could provide a way to reconcile the different approaches to drug discovery and validation in epilepsy, and a brighter future for patients.
Catherine M. Abbott, Associate Editor
Published: April 17, 2019 2080
DOI: 10.1021/acschemneuro.9b00162 ACS Chem. Neurosci. 2019, 10, 2080−2081
ACS Chemical Neuroscience
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Editorial
AUTHOR INFORMATION
ORCID
Catherine M. Abbott: 0000-0001-8794-7173 Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) Helbig, I., et al. (2016) Primer Part 1-The building blocks of epilepsy genetics. Epilepsia 57 (6), 861−8. (2) Wolff, M., et al. (2017) Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 140 (5), 1316−1336. (3) Mullen, S. A., et al. (2018) Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine. Neurology 90 (1), e67−e72. (4) Copmans, D., et al. (2018) Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A. ACS Chem. Neurosci. 9 (7), 1652−1662. (5) Kaufmann, K., et al. (2013) ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice. ACS Chem. Neurosci. 4 (9), 1278−86. (6) Kortagere, S., et al. (2018) Identification of Novel Allosteric Modulators of Glutamate Transporter EAAT2. ACS Chem. Neurosci. 9 (3), 522−534. (7) Delahaye-Duriez, A., et al. (2016) Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery. Genome Biol. 17 (1), 245.
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DOI: 10.1021/acschemneuro.9b00162 ACS Chem. Neurosci. 2019, 10, 2080−2081
