The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol

Vespa, Paul; Shrestha, Vikesh; Abend, Nicholas S.; Agoston, Denes V.; Au, Alicia K.; Bell, Michael J.; Bleck, Thomas P.; Blanco, Manuel Buitrago; Claassen, Jan; Duncan, Dominique; Ellingson, Ben; Foreman, Brandon; Gilmore, Emily J.; Hirsch, Lawrence J.; Hunn, Martin; Kamnaksh, Alaa; McArthur, David L.; Morokoff, Andrew; O’Brien, Terence J.; O’Phelan, Kristine; Robertson, Courtney; Rosenthal, Eric S.; Staba, Richard J.; Toga, Arthur W.; Willyerd, Frederick; Zimmermann, Lara; Yam, Elisa; Martínez, Susana; Real, Courtney; Engel, Jerome

doi:10.1016/j.nbd.2018.07.025

Cited by 38 publications

(44 citation statements)

References 16 publications

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“…Furthermore, there is active effort to discover biomarkers of disease development (epileptogenesis) and surrogate efficacy biomarkers. Availability of such biomarkers would facilitate comparison of results across different models and translation to clinical preventive studies . Let us hope that the next few years will yield results that will lead to human epilepsy prevention studies—before the authors retire.…”

Section: Summary/conclusionmentioning

confidence: 99%

“…Availability of such biomarkers would facilitate comparison of results across different models and translation to clinical preventive studies. 292 Let us hope that the next few years will yield results that will lead to human epilepsy prevention studies-before the authors retire. It is interesting to note that some pharmaceutical companies currently plan epilepsy prevention trials based on promising preclinical data on clinically approved drugs, for instance with eslicarbazepine acetate for poststroke epilepsy.…”

Section: Summary/conclusionmentioning

confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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Section: Summary/conclusionmentioning

confidence: 99%

Section: Summary/conclusionmentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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“…Considerable efforts ongoing in this regard include EPITARGET (Targets and Biomarkers for Anti‐epileptogenesis) (EPITARGET ) and EpiBioS4Rx (Epilepsy Bioinformatics Study for Anti‐Epileptogenic Therapy) (Vespa et al . ). EPITARGET is focusing mainly on identifying novel biomarkers and exploring the involvement of multiple mechanisms that might contribute to the process of epileptogenesis (EPITARGET ).…”

mentioning

confidence: 97%

“…Currently, huge efforts have been made to understand the pathogenesis of epileptogenesis, and the pathways associated with epileptogenesis which exhibits great potentials in treating epilepsy. Considerable efforts ongoing in this regard include EPITARGET (Targets and Biomarkers for Anti-epileptogenesis) (EPITAR-GET 2018) and EpiBioS4Rx (Epilepsy Bioinformatics Study for Anti-Epileptogenic Therapy) (Vespa et al 2018). EPI-TARGET is focusing mainly on identifying novel biomarkers and exploring the involvement of multiple mechanisms that might contribute to the process of epileptogenesis (EPITARGET 2018).…”

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confidence: 99%

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Paudel

Semple

Jones

et al. 2019

Journal of Neurochemistry

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Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti‐epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1‐targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.

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“…Pre-clinical plasma samples were quality controlled using the same hemoglobin variant, hemoglobin subunit alpha 1, used to QC clinical samples at the Biospecimen Exchange for Neurological Disorders (BioSEND; Indiana University, Bloomington, IN, USA) (Vespa et al, 2018). Secondary QC of rat plasma samples was conducted at the Uniformed Services University (USU; Bethesda, MD, USA) using RPPM as described in detail (section 2.2).…”

Section: Methodsmentioning

confidence: 99%

Harmonization of pipeline for preclinical multicenter plasma protein and miRNA biomarker discovery in a rat model of post-traumatic epileptogenesis

et al. 2019

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The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is an international, multicenter, multidisciplinary study aimed at preventing epileptogenesis (https://epibios.loni.usc.edu/). One of the study’s major objectives is the discovery of diagnostic, prognostic, and predictive plasma protein and microRNA (miRNA) biomarkers that are sensitive, specific, and translatable to the human condition. Epilepsy due to structural brain abnormalities, secondary to neurological insults such as traumatic brain injury (TBI), currently represents ~50% of all epilepsy cases. In the preclinical EpiBioS4Rx study, TBI was induced in adult male Sprague Dawley rats using a standardized protocol for lateral fluid-percussion injury. Whole blood was collected from the tail vein at baseline and 2, 9 and 30 days post-injury and processed for plasma separation. Biomaterial properties, sample preparation and integrity, and choice of analysis platform can significantly impact measured marker levels and, in turn, interpretation with respect to injury and/or other variables. We present here the results of procedural harmonization for the first 320 rats included in the EpiBioS4Rx study, from three international research centers, and preliminary proteomic and miRNA analyses. We also discuss experimental considerations for establishing rigorous quality controls with the goal of harmonizing operating procedures across study sites, and delivering high-quality specimens for preclinical biomarker discovery in a rat model of post-traumatic epilepsy (PTE).

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The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol

Cited by 38 publications

References 16 publications

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Harmonization of pipeline for preclinical multicenter plasma protein and miRNA biomarker discovery in a rat model of post-traumatic epileptogenesis

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