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EPITARGET Report Summary

Project ID: 602102
Funded under: FP7-HEALTH
Country: Sweden

Periodic Report Summary 3 - EPITARGET (Targets and biomarkers for antiepileptogenesis)

Project Context and Objectives:
EPITARGET is a large European consortium of universities, research institutions and SMEs dedicated to understand complex mechanisms and identify biomarkers of epileptogenesis to improve treatment and diagnosis of epilepsy. The overall scientific objectives of EPITARGET are:
Using multidisciplinary strategies of basic, preclinical and clinical research to
1. identify novel biomarkers and their combinations that will define the different stages of epileptogenesis and predict/diagnose early and late stages of the evolution of the disease. This will pave the way to improved diagnostics and better patient stratification, as well as development of patient-specific preventive strategies. In this objective EPITARGET will identify at least 2 biomarkers that in combination will predict whether epileptogenesis is triggered in post-insult period and will stratify those individual subjects that are at risk of developing epilepsy.
2. unravel the complex patho-physiology of epileptogenesis and to design new, disease-modifying combinatorial treatment strategies specifically targeted to the different stages of epileptogenesis. These novel treatment strategies are expected to be capable of preventing the development of epilepsy in at-risk patients and stop its progression after the onset of the disease. Different epileptogenesis-associated processes, such as brain damage and structural/functional reorganization, neurogenesis, BBB dysfunction, inflammation, free radical formation, genetic and epigenetic alterations will be individually addressed and specific treatments directly or indirectly targeting these mechanisms will be combined. The choice of the best combinatorial therapeutic strategy will be assisted by systems biology approaches. This strategy will help to identify key aetiological factors thus limiting redundancy in the choice of multiple drug targets and facilitating rational drug discovery process. In this objective EPITARGET will identify at least 2 patho-physiological mechanisms of epileptogenesis that will be targeted in combination in animal subjects at risk of developing epilepsy (post-insult period).
3. translate the knowledge obtained in experimental models to patients in order to improve diagnosis, achieve better patient stratification, and develop new antiepileptogenic treatments and means to predict their efficacy. The objective is to verify and validate biomarkers in blood and brain tissue samples obtained from patients after potentially epileptogenic brain insults. These tissues include TBI and post-mortem brain tissue from patients that had SE or TBI (early-stage epileptogenesis), as well as from those with chronic epilepsy. These specimens are the best closest match to the experimental brain tissue of post-insult epileptogenesis in animal models. In this objective EPITARGET will perform clinical validation of the combinatorial biomarker approach (objective 1), and thereby obtain data from patients to prove the concept for future clinical applications.
To achieve these objectives and maximise outcome, EPITARGET tackles the complexity of epileptogenesis by adopting concerted and complementary actions of participating partners, attacking various aspects of epileptogenesis at different levels. EPITARGET combines a powerful arsenal of both established and innovative multidisciplinary research strategies, tools and platforms. Analysis of data is assisted by creating an animal and human database, and a bioinformatics approach within the consortium.

Project Results:
EPITARGET developed Epilepsy Preclinical Biomarker Bank Case Report Forms containing the Common Data Elements and Guidelines for procedures of experimental work, which were published on the EPITARGET webpage and in Epilepsy Research (Lapinlampi et al, 2016).
A list of plasma biomarkers for epileptogenesis is being generated by EPITARGET Partners. EPITARGET is currently running a longitudinal study to investigate alterations in plasma miRNA levels in different refined models of epilepsy, in which only a subset of animals develop spontaneous seizures after an epileptogenic insult.
Some inflammatory biomarkers were monitored using PET, enabling calculation of neuroinflammation time course after status epilepticus (SE). Some new tracers have been also developed to monitor blood-brain barrier leakage during epileptogenesis.
EPITARGET completed the testing phase of novel MRI approaches. Also, novel implantable RF-coil approach combining EEG and MRI was developed.
EPITARGET developed an electronic organic micropump for local drug delivery, while recording electrophysiological activity from the delivery site (Jonnson et al., PNAS 2016).
Lipidomic analysis in the hippocampus of mice during epileptogenesis demonstrate changes in the profile of distinct lipid mediators. Next generation sequencing analysis showed that several miRNAs were up- or downregulated during the acute, latent and chronic phase in rat plasma.
The expression of proteasome subunits in the post-SE rat model and in human epileptic brain tissue has been completed.
Microglia activation and astrocytosis arise in the retina following SE, thus highlighting a potential biomarker of neuroinflammation.
The setup of a novel combination of anti-oxidant drugs to reduce oxidative stress post-SE has been accomplished. The combined treatment reduced oxidative stress more efficiently than either drug alone.
Extracellular matrix (ECM) molecules have been shown to affect synaptic transmission and plasticity in the hippocampus. Gain- and loss-of-function approaches demonstrate possible role of ECM in synaptic plasticity.
A combination of phenotypic biomarkers, including seizure threshold and behavioral hyper-excitability, are predictive of epilepsy development in the lithium/pilocarpine model in rats.
For testing tolerability of drug combinations, an algorithm was developed by which combinations of 2-3 drugs are tested at different doses in naive rodents and, if tolerable, these combinations are then evaluated in epileptic rodents. (Klee et al., Epilepsy Res., 2015).
To target therapeutic molecules into the brain, more stable amplicon vectors were developed, which were tested in mouse hippocampus for long-term expression of the transgene. Amplification and purification rounds are now carried on to obtain large purified and concentrated batches of the combinatorial amplicon vectors that will be tested in various animal models. The SME Bioviron is working to establish the best plan towards translational therapeutic applications.
EPITARGET established the ‘virtual human brain tissue database’, containing very dense and high quality clinical and neuropathological data.
EPITARGET observed a significant increase of the single nucleotide polymorphism in epilepsy-associated glioneuronal neoplasms that resemble neuropathological features of focal cortical dysplasia (Robens et al., Life Sci 2016).
Systems genetics approaches characterized the genetic regulation of pathophysiological pathways in human TLE.
EPITARGET used a combinatorial approach starting from large-scale gene expression from biopsy hippocampi and corresponding genetic data from a large series of pharmacoresistant TLE patients (Bungenberg et al., Neurobiol Dis 2016).
Major results for dissemination were the generation of a major review paper published in Lancet Neurology, 2016 (Pitkanen et al.), the organization of the 2nd EPITARGET Young Researchers’ Symposium and the launch and continuous maintenance of the EPITARGET Website and Facebook page.

Potential Impact:
The overall expected final results of EPITARGET are to (i) identify combinatorial biomarkers for epileptogenesis, diagnostics, prediction of disease progression and pharmacoresistance; (i) identify combinatorial preventive and disease-modifying treatments targeting complex pathophysiological mechanisms of post-insult epileptogenesis; and (iii) validate combinatorial biomarkers from animal studies in human subjects and tissue. These results are envisaged to have a dramatic impact on the socio-economic burden of epilepsy by improving quality of life for millions of people and their families, reducing the costs related to epilepsy, currently estimated as 20 billion € for Europe only. Societal implications of the final results of EPITARGET are expected to have significant influence on a wide range of areas including patient and professional organizations, professionals in clinical practice, regulatory authorities, pharmacological industries and SMEs, funding organizations, other brain diseases, as well as on health status of the general population.
Objective 1:
Establishing Epilepsy Preclinical Biomarker Bank (EPBB) and database will have an impact not only on the outcomes of EPITARGET, but will have wider implications for the epilepsy research community, as well as for other areas of neurological diseases. This will be one of the first animal biobanks and databases that will lay a foundation for other disease model biobanks, facilitating the preclinical research. CDEs and CRFs, which are already developed and published by EPITARGET on the website and in Epilepsy Research (2016), will be valuable for ILAE task force dedicated for this mission, as well as for other consortia in epilepsy established in USA by NINDS initiative for Centers Without Walls (CWOW).
Objective 2:
EPITARGET has already generated data on temporal and spatial patterns of gene and protein expression for a wide range of factors and molecules potentially involved in epileptogenesis, which is broadening our understanding of epileptogenesis, and eventually will result in developing combinatorial antiepileptogenic treatment strategies.
Results obtained during the first 3 years of EPITARGET in evaluating combinatorial treatment approaches based on existing drugs and novel compounds have an impact on shifting the paradigm of thinking about possibilities for preventive and disease modifying treatment strategies after brain insults. Novel drug combinations are also generating results and will increase our knowledge and understanding of antiepileptogenic treatment possibilities. Moreover, results on optimization and standardization of post-SE animal models are very useful not only for EPITARGET but the whole epilepsy research community, and will contribute for more understanding of those factors, such as animal strain and batch variability, SE duration and termination procedures, site of insults of the brain, etc., in contributing variable outcomes of the preclinical studies.
Large capacity Amplicon viral vectors and other novel brain delivery strategies that are being validated by EPITARGET will open novel avenues for combinatorial treatment approaches in preventing epileptogenesis and disease progression, and contribute to innovative thinking and exploitation of the results for commercialization strategies of SMEs.
Objective 3:
Ongoing prospective collection of samples from brain tissue, imaging, EEG and fluids from TBI and epilepsy patients will have a crucial role in securing validation of animal data in human material, paving foundation for translational research and clinical applications. Inclusion of patient data, and establishment of sample collection logistical details secures timely progress of validation process envisaged by EPITARGET. This material can also be used for data mining and systems biology approaches, and may also has led to the process of human biobank development, which will have significant impact on the research possibilities even outside EPITARGET.

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