112 results found
Olona A, Hateley C, Guerrero A, et al., 2022, Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis, British Journal of Pharmacology, Vol: 179, Pages: 1874-1886, ISSN: 0007-1188
Background and purpose: Cardiac glycosides (CGs) inhibit the Na+,K+‐ATPase and are widely prescribed medicines for chronic heart failure and cardiac arrhythmias. Recently, CGs have been described to induce inflammasome activation and pyroptosis in human macrophages, suggesting a cytotoxicity that remains to be elucidated in tissues.Experimental approach: To determine the cell type specificity of CG‐mediated cytotoxicity, we used human primary monocyte‐derived macrophages (hMDMs) and non‐adherent peripheral blood cells isolated from healthy donors. Omental white adipose tissue (WAT) and stromal vascular fraction (SVF)‐derived pre‐adipocytes and adipocytes were isolated from obese patients undergoing bariatric surgery. All these primary cells/tissues were treated with nanomolar concentrations of ouabain (50nM, 100nM and 500nM) to investigate its degree of cytotoxicity and mechanisms leading to cell death. In WAT, we further explored the consequences of ouabain‐mediated cytotoxicity by measuring insulin sensitivity, adipose tissue function and extracellular matrix (ECM) deposition ex vivo.Key results: The ouabain‐induced cell death is through pyroptosis and apoptosis, and more efficient in hMDMs compared to non‐adherent PBMC populations. This selective cytotoxicity is dependent on K+ flux, as ouabain causes an intracellular depletion of K+, while inducing accumulation of Na+ and Ca2+ levels. Consistently, the cell‐death caused by these ion imbalances can be rescued by addition of potassium chloride in hMDMs. Remarkably, when WAT explants from obese patients are cultured with nanomolar concentrations of ouabain, this causes depletion of macrophages, down‐regulation of type VI collagen levels, and amelioration of insulin sensitivity ex vivo.Conclusions and implications: These results suggest that the usage of nanomolar concentration of CGs can be an attractive therapeutic avenue in metabolic syndrome characterised by pathogenic infiltration and activation of macrophages.
Campbell C, Lewis-Smith D, Leu C, et al., 2022, Polygenic risk score analysis reveals shared genetic burden between epilepsy and psychiatric comorbidities, Publisher: SPRINGERNATURE, Pages: 31-32, ISSN: 1018-4813
Meijer M, Agirre E, Kabbe M, et al., 2022, Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility, Neuron, Vol: 110, Pages: 1193-1210.e13, ISSN: 0896-6273
Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-γ) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-γ leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological-based therapies for MS.
Motelow JE, Povysil G, Dhindsa RS, et al., 2021, Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals, The American Journal of Human Genetics, Vol: 108, Pages: 2024-2024, ISSN: 0002-9297
De T, Goncalves A, Speed D, et al., 2021, Signatures of TSPAN8 variants associated with human metabolic regulation and diseases, iScience, Vol: 24, ISSN: 2589-0042
Here, with the example of common copy number variation (CNV) in the TSPAN8 gene, we present an important piece of work in the field of CNV detection, that is, CNV association with complex human traits such as 1H NMR metabolomic phenotypes and an example of functional characterization of CNVs among human induced pluripotent stem cells (HipSci). We report TSPAN8 exon 11 (ENSE00003720745) as a pleiotropic locus associated with metabolomic regulation and show that its biology is associated with several metabolic diseases such as type 2 diabetes (T2D) and cancer. Our results further demonstrate the power of multivariate association models over univariate methods and define metabolomic signatures for variants in TSPAN8.
Feleke R, Reynolds RH, Smith AM, et al., 2021, Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases, Acta Neuropathologica, Vol: 142, Pages: 449-474, ISSN: 0001-6322
Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular "window" of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.
Wolking S, Campbell C, Stapleton C, et al., 2021, Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications, FRONTIERS IN PHARMACOLOGY, Vol: 12, ISSN: 1663-9812
Wolking S, Moreau C, McCormack M, et al., 2021, Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy, ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, Vol: 8, Pages: 1376-1387, ISSN: 2328-9503
Allen AS, Aggarwal V, Berkovic SF, et al., 2021, Diverse genetic causes of polymicrogyria with epilepsy, EPILEPSIA, Vol: 62, Pages: 973-983, ISSN: 0013-9580
Schijven D, Stevelink R, McCormack M, et al., 2020, Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy, Neurobiology of Aging, Vol: 92, Pages: 153.e1-153.e5, ISSN: 0197-4580
Wolking S, Schulz H, Nies AT, et al., 2020, Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study, PHARMACOGENOMICS, Vol: 21, Pages: 325-335, ISSN: 1462-2416
Kobow K, Reid CA, van Vliet EA, et al., 2020, Epigenetics explained: a topic "primer" for the epilepsy community by the ILAE Genetics/Epigenetics Task Force, EPILEPTIC DISORDERS, Vol: 22, Pages: 127-141, ISSN: 1294-9361
Wolking S, Moreau C, Nies AT, et al., 2020, Testing association of rare genetic variants with resistance to three common antiseizure medications, Epilepsia, Vol: 61, Pages: 657-666, ISSN: 0013-9580
OBJECTIVE: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). METHODS: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. RESULTS: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. SIGNIFICANCE: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.
Schidlitzki A, Bascuñana P, Srivastava PK, et al., 2020, Proof-of-concept that network pharmacology is effective to modify development of acquired temporal lobe epilepsy, Neurobiology of Disease, Vol: 134, Pages: 1-16, ISSN: 0969-9961
Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetiracetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functional network of epilepsy-relevant proteins. Using the intrahippocampal kainate mouse model of temporal lobe epilepsy, the drug combination was administered during the latent period before onset of spontaneous recurrent seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single drug treatment. Furthermore, a combination of levetiracetam and phenobarbital, for which in silico analysis of drug-protein interaction networks did not indicate any significant drug-drug interaction, was not effective to modify development of epilepsy. Surprisingly, the promising antiepileptogenic effect of the levetiracetam/topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multimodal brain imaging and histopathology. High throughput RNA-sequencing (RNA-seq) of the ipsilateral hippocampus of mice treated with the levetiracetam/topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of epilepsy.
Miller TD, Chong TT-J, Aimola Davies AM, et al., 2020, Human hippocampal CA3 damage disrupts both recent and remote episodic memories, eLife, Vol: 9, ISSN: 2050-084X
Neocortical-hippocampal interactions support new episodic (event) memories, but there is conflicting evidence about the dependence of remote episodic memories on the hippocampus. In line with systems consolidation and computational theories of episodic memory, evidence from model organisms suggests that the cornu ammonis 3 (CA3) hippocampal subfield supports recent, but not remote, episodic retrieval. In this study, we demonstrated that recent and remote memories were susceptible to a loss of episodic detail in human participants with focal bilateral damage to CA3. Graph theoretic analyses of 7.0-Tesla resting-state fMRI data revealed that CA3 damage disrupted functional integration across the medial temporal lobe (MTL) subsystem of the default network. The loss of functional integration in MTL subsystem regions was predictive of autobiographical episodic retrieval performance. We conclude that human CA3 is necessary for the retrieval of episodic memories long after their initial acquisition and functional integration of the default network is important for autobiographical episodic memory performance.
Johnson MR, 2020, Re: Time to move beyond genetics towards biomedical data-driven translational genomic research in severe paediatric epilepsies., European Journal of Paediatric Neurology, Vol: 24, Pages: 4-4, ISSN: 1090-3798
Heavin SB, McCormack M, Wolking S, et al., 2019, Genomic and clinical predictors of lacosamide response in refractory epilepsies, Epilepsia Open, Vol: 4, Pages: 563-571, ISSN: 2470-9239
Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. Results: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis. Significance: No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.
Johnson MR, Kaminski RM, 2019, A systems-level framework for anti-epilepsy drug discovery, Neuropharmacology, Vol: 170, Pages: 1-15, ISSN: 0028-3908
Modern anti-seizure drug development yielded benefits in terms of improved pharmacokinetics, safety and tolerability profiles, but offered no advances in efficacy compared to previous older generations of anti-seizure drugs. Despite significant advances in our understanding of the genetic bases to epilepsy, and a welcome renewed interest on the severe monogenic epilepsies, modern genetics has yet to directly inform more effective or disease-modifying anti-seizure drugs. Here, we describe a new approach to the identification of novel disease modifying anti-epilepsy drugs. The systems genetics approach aims to first identify pathophysiological mechanisms by integrating polygenic risk with cellular gene expression profiles and then to relate these molecular mechanisms to druggable targets using a gene regulatory (regulome) framework. The approach offers an exciting and flexible framework for future drug discovery in epilepsy, and is applicable to any disease for which appropriate cell-type and disease-context specific data exist.
Leu C, Stevelink R, Smith AW, et al., 2019, Polygenic burden in focal and generalized epilepsies., Brain, Vol: 142, Pages: 3473-3481
Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish Europ
Laaniste L, Srivastava P, Stylianou T, et al., 2019, Integrated systems-genetic analyses reveal a network target for delaying glioma progression, Annals of Clinical and Translational Neurology, Vol: 6, Pages: 1616-1638, ISSN: 2328-9503
ObjectiveTo identify a convergent, multitarget proliferation characteristic for astrocytoma transformation that could be targeted for therapy discovery.MethodsUsing an integrated functional genomics approach, we prioritized networks associated with astrocytoma progression using the following criteria: differential co‐expression between grade II and grade III IDH1‐mutated and 1p/19q euploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patient survival and sample‐level genomic features. Drugs targeting the identified multitarget network characteristic for astrocytoma transformation were computationally predicted using drug transcriptional perturbation data and validated using primary human astrocytoma cells.ResultsA single network, M2, consisting of 177 genes, was associated with glioma progression on the basis of the above criteria. Functionally, M2 encoded physically interacting proteins regulating cell cycle processes and analysis of genome‐wide gene‐regulatory interactions using mutual information and DNA–protein interactions revealed the known regulators of cell cycle processes FoxM1, B‐Myb, and E2F2 as key regulators of M2. These results suggest functional disruption of M2 via gene mutation or altered expression as a convergent pathway regulating astrocytoma transformation. By considering M2 as a multitarget drug target regulating astrocytoma transformation, we identified several drugs that are predicted to restore M2 expression in anaplastic astrocytoma toward its low‐grade profile and of these, we validated the known antiproliferative drug resveratrol as down‐regulating multiple nodes of M2 including at nanomolar concentrations achievable in human cerebrospinal fluid by oral dosing.InterpretationOur results identify M2 as a multitarget network characteristic for astrocytoma progression and encourage M2‐based drug screening to identify new compounds for preventing glioma transformation.
Silvennoinen K, de Lange N, Zagaglia S, et al., 2019, Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy, Epilepsia Open, Vol: 4, Pages: 420-430, ISSN: 2470-9239
Objective: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). Significance: In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. Wi
Feng Y-CA, Howrigan DP, Abbott LE, et al., 2019, Ultra-rare genetic variation in the epilepsies: A whole-exome sequencing study of 17,606 individuals, The American Journal of Human Genetics, Vol: 105, Pages: 267-282, ISSN: 0002-9297
Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Berghuis B, Stapleton C, Sonsma ACM, et al., 2019, A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine, Epilepsia Open, Vol: 4, Pages: 102-109, ISSN: 2470-9239
Epilepsia Open published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy. Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.
Silvennoinen K, de Lange N, Zagaglia S, et al., 2018, Retrospective Analysis Of Antiepileptic Drug Effectiveness And Tolerability In Juvenile Myoclonic Epilepsy, 13th European Congress on Epileptology, Publisher: WILEY, Pages: S219-S220, ISSN: 0013-9580
The International League Against Epilepsy Consortium on Complex Epilepsies, 2018, Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies, Nature Communications, Vol: 9, ISSN: 2041-1723
The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Srivastava P, van Eyll J, Godard P, et al., 2018, A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target, Nature Communications, Vol: 9, ISSN: 2041-1723
The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”—CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy.
May P, Girard S, Harrer M, et al., 2018, Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies: an exome-based case-control study, Lancet Neurology, Vol: 17, Pages: 699-708, ISSN: 1474-4422
BackgroundGenetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.MethodsFor this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FindingsStatistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare mis
McCormack M, Gui H, Ingason A, et al., 2017, Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients, NEUROLOGY, Vol: 90, Pages: E332-E341, ISSN: 0028-3878
Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed.Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients.Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.
Srivastava PK, Roncon P, Lukasiuk K, et al., 2017, Meta-Analysis of MicroRNAs Dysregulated in the Hippocampal Dentate Gyrus of Animal Models of Epilepsy., eNeuro, Vol: 4, ISSN: 2373-2822
The identification of mechanisms transforming normal to seizure-generating tissue after brain injury is key to developing new antiepileptogenic treatments. MicroRNAs (miRNAs) may act as regulators and potential treatment targets for epileptogenesis. Here, we undertook a meta-analysis of changes in miRNA expression in the hippocampal dentate gyrus (DG) following an epileptogenic insult in three epilepsy models. We identified 26 miRNAs significantly differentially expressed during epileptogenesis, and five differentially expressed in chronic epilepsy. Of these, 13 were not identified in any of the individual studies. To assess the role of these miRNAs, we predicted their mRNA targets and then filtered the list to include only target genes expressed in DG and negatively correlated with miRNA expression. Functional enrichment analysis of mRNA targets of miRNAs dysregulated during epileptogenesis suggested a role for molecular processes related to inflammation and synaptic function. Our results identify new miRNAs associated with epileptogenesis from existing data, highlighting the utility of meta-analysis in maximizing value from preclinical data.
van Vliet EA, Puhakka N, Mills JD, et al., 2017, Standardization procedure for plasma biomarker analysis in rat models of epileptogenesis: Focus on circulating microRNAs., Epilepsia, Vol: 58, Pages: 2013-2024, ISSN: 0013-9580
The World Health Organization estimates that globally 2.4 million people are diagnosed with epilepsy each year. In nearly 30% of these cases, epilepsy cannot be properly controlled by antiepileptic drugs. More importantly, treatments to prevent or modify epileptogenesis do not exist. Therefore, novel therapies are urgently needed. In this respect, it is important to identify which patients will develop epilepsy and which individually tailored treatment is needed. However, currently, we have no tools to identify the patients at risk, and diagnosis of epileptogenesis remains as a major unmet medical need, which relates to lack of diagnostic biomarkers for epileptogenesis. As the epileptogenic process in humans is typically slow, the use of animal models is justified to speed up biomarker discovery. We aim to summarize recommendations for molecular biomarker research and propose a standardized procedure for biomarker discovery in rat models of epileptogenesis. The potential of many phylogenetically conserved circulating noncoding small RNAs, including microRNAs (miRNAs), as biomarkers has been explored in various brain diseases, including epilepsy. Recent studies show the feasibility of detecting miRNAs in blood in both experimental models and human epilepsy. However, the analysis of circulating miRNAs in rodent models is challenging, which relates both to the lack of standardized sampling protocols and to analysis of miRNAs. We will discuss the issues critical for preclinical plasma biomarker discovery, such as documentation, blood and brain tissue sampling and collection, plasma separation and storage, RNA extraction, quality control, and RNA detection. We propose a protocol for standardization of procedures for discovery of circulating miRNA biomarkers in rat models of epileptogenesis. Ultimately, we hope that the preclinical standardization will facilitate clinical biomarker discovery for epileptogenesis in man.
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