Abstracts

Rationale:
Hypothalamic hamartomas (HHs) are rare developmental malformations, clinically associated with “gelastic” or “dacrystic” focal seizures, focal seizures or a generalized epileptic encephalopathy 1-4. Surgical approaches still remain the mainstay of therapy for these lesions, as seizures associated with these subcortical lesions frequently remain refractory to both medical therapy and other alternative approaches such as  ketogenic diet, and vagal nerve stimulation 3-5. However, surgical approaches remain limited due to the proximity of the lesions with critical vascular and eloquent neural structures 1, 3, 5. Here, we exploit genetic databases via an “in silico” approach to identify novel therapeutic targets that can be used for treating seizures associated with HHs.
Method:
We queried the Genecards database (https://www.genecards.org/), that integrates information from >90 data resources to identify all genes identified to date in HHs and epilepsy. We then utilized the Network Data Exchange (NDEx,) (www.ndexbio.org), to identify shared genes involved in both HHs and epilepsy. Common genes identified were then queried in the Drug Bank database to identify possible drug candidates.
Results:
Our initial search yielded 354 genes for HHs and 5064 genes associated with epilepsy. A search for mutual genes between the two pathways resulted in 253 genes, with a relevance score between 0.5 and 60.0. A possible network for epileptogenicity in HHs was then mapped by utilizing the NDEx that consolidates information from the National Cancer Institute (NCI) pathway Interaction Database, Pathway Commons, and the Open Biological Expression Language (BEL) Consortium. This network was then interrogated on the Drug Bank database to identify possible drug targets. A list of 90 possible target nodes were identified. We next honed our search towards enzyme targeting molecules that were directed towards six shared enzymatic targets (Fig 1). Of particular interest, cannabidiol (CBD) was identified as a possible target, raising the hypothesis that CBD might be efficacious in treating refractory seizures associated with HHs. Some other candidates of interest that came up as possible “hits” include steroids like dexamethasone, and betamethasone, the progesterone agonist, levonorgestrel, the anti-leprosy drug, dapsone, the anti-malarial drug, mefloquine, the mu agonist, methadone and the TRPV-1 channel inhibitor, capsaicin. While our strategy is limited by a lack of “wet lab” experiments, we believe this approach is powerful in identifying future therapeutic targets for the relatively rare HHs.
Conclusion:
We describe an “in silico” strategy for identifying therapeutic targets in seizures associated with HHs. We have identified many possible candidates of interest, that are known drug molecules, that modulate mutual enzyme shared targets between HHs and epilepsy. Our study lays the ground work for future experiments that validate the definitive role of these drug targeting molecules in seizures associated with HHs.
Funding:
:N/A