Precision Treatments in Epilepsy.
Ontology highlight
ABSTRACT:
SUBMITTER: Demarest S
PROVIDER: S-EPMC8608958 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Precision medicine is an old concept, but it is not widely applied across human health conditions as yet. Numerous attempts have been made to apply precision medicine in epilepsy, this has been based on a better understanding of aetiological mechanisms and deconstructing disease into multiple biological subsets. The scope of precision medicine is to provide effective strategies for treating individual patients with specific agent(s) that are likely to work best based on the causal biological make-up. We provide an overview of the main applications of precision medicine in epilepsy, including the current limitations and pitfalls, and propose potential strategies for implementation and to achieve a higher rate of success in patient care. Such strategies include establishing a definition of precision medicine and its outcomes; learning from past experiences, from failures and from other fields (e.g. oncology); using appropriate precision medicine strategies (e.g. drug repurposing versus traditional drug discovery process); and using adequate methods to assess efficacy (e.g. randomised controlled trials versus alternative trial designs). Although the progress of diagnostic techniques now allows comprehensive characterisation of each individual epilepsy condition from a molecular, biological, structural and clinical perspective, there remain challenges in the integration of individual data in clinical practice to achieve effective applications of precision medicine in this domain.
| S-EPMC10590329 | biostudies-literature
Project description:Cigarette smoking is highly addictive and modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings to clinical practice is identifying the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. We reviewed the significant genetic variants that predict nicotine dependence, smoking cessation, and response to cessation pharmacotherapy. These data suggest that genetic risks can predict smoking cessation outcomes and moderate the effect of pharmacological treatments. Some pharmacogenetic findings have been replicated in meta-analyses or in multiple smoking cessation trials. The variation in efficacy between smokers with different genetic markers supports the notion that personalized smoking cessation intervention based upon genotype could maximize the efficiency of such treatment while minimizing side effects, thus influencing the number needed to treat (NNT) and the number needed to harm. In summary, as precision medicine is revolutionizing healthcare, smoking cessation may be one of the first areas where genetic variants may identify individuals at increased risk. Current evidence strongly suggests that genetic variants predict cessation failure and that cessation pharmacotherapy effectiveness is modulated by biomarkers such as nicotinic cholinergic receptor ?5 subunit (CHRNA5) genotypes or nicotine metabolism ratio (NMR). These findings strengthen the case for the development and rigorous testing of treatments that target patients with different biological risk profiles.
| S-EPMC5115988 | biostudies-literature
Project description:Malformations of cortical development (MCDs) represent a range of neurodevelopmental disorders that are collectively common causes of developmental delay and epilepsy, especially refractory childhood epilepsy. Initial treatment with antiseizure medications is empiric, and consideration of surgery is the standard of care for eligible patients with medically refractory epilepsy. In the past decade, advances in next generation sequencing technologies have accelerated progress in understanding the genetic etiologies of MCDs, and precision therapies for focal MCDs are emerging. Notably, mutations that lead to abnormal activation of the mammalian target of rapamycin (mTOR) pathway, which provides critical control of cell growth and proliferation, have emerged as a common cause of malformations. These include tuberous sclerosis complex (TSC), hemimegalencephaly (HME), and some types of focal cortical dysplasia (FCD). TSC currently represents the best example for the pathway from gene discovery to relatively safe and efficacious targeted therapy for epilepsy related to MCDs. Based on extensive pre-clinical and clinical data, the mTOR inhibitor everolimus is currently approved for the treatment of focal refractory seizures in patients with TSC. Although clinical studies are just emerging for FCD and HME, we believe the next decade will bring significant advancements in precision therapies for epilepsy related to these and other MCDs.
| S-EPMC8608994 | biostudies-literature
Project description:The mechanistic target of rapamycin signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mechanistic target of rapamycin cascade funnels through mechanistic target of rapamycin complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mechanistic target of rapamycin complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mechanistic target of rapamycin regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mechanistic target of rapamycin pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mechanistic target of rapamycin complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively, the mTORopathies are characterized by excessive mechanistic target of rapamycin pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalized medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mechanistic target of rapamycin pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mechanistic target of rapamycin inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.
| S-EPMC8495134 | biostudies-literature
Project description:Epilepsy includes a number of medical conditions with recurrent seizures as common denominator. The large number of different syndromes and seizure types as well as the highly variable inter-individual response to the therapies makes management of this condition often challenging. In the last two decades, a genetic etiology has been revealed in more than half of all epilepsies and single gene defects in ion channels or neurotransmitter receptors have been associated with most inherited forms of epilepsy, including some focal and lesional forms as well as specific epileptic developmental encephalopathies. Several genetic tests are now available, including targeted assays up to revolutionary tools that have made sequencing of all coding (whole exome) and non-coding (whole genome) regions of the human genome possible. These recent technological advances have also driven genetic discovery in epilepsy and increased our understanding of the molecular mechanisms of many epileptic disorders, eventually providing targets for precision medicine in some syndromes, such as Dravet syndrome, pyroxidine-dependent epilepsy, and glucose transporter 1 deficiency. However, these examples represent a relatively small subset of all types of epilepsy, and to date, precision medicine in epilepsy has primarily focused on seizure control, and other clinical aspects, such as neurodevelopmental and neuropsychiatric comorbidities, have yet been possible to address. We herein summarize the most recent advances in genetic testing and provide up-to-date approaches for the choice of the correct test for some epileptic disorders and tailored treatments that are already applicable in some monogenic epilepsies. In the next years, the most probably scenario is that epilepsy treatment will be very different from the currently almost empirical approach, eventually with a "precision medicine" approach applicable on a large scale.
| S-EPMC7283411 | biostudies-literature
Project description: Not available
| S-EPMC9237755 | biostudies-literature
Project description:Post-traumatic epilepsy (PTE) is diagnosed in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments.
| S-EPMC6309524 | biostudies-literature
Project description:Brain stimulation is an alternative treatment for epilepsy. However, the neuronal circuits underlying its mechanisms remain obscure. We found that optogenetic activation (1Hz) of entorhinal calcium/calmodulin-dependent protein kinase II α (CaMKIIα)-positive neurons, but not GABAergic neurons, retarded hippocampal epileptogenesis and reduced hippocampal seizure severity, similar to that of entorhinal low-frequency electrical stimulation (LFES). Optogenetic inhibition of entorhinal CaMKIIα-positive neurons blocked the antiepileptic effect of LFES. The channelrhodopsin-2-eYFP labeled entorhinal CaMKIIα-positive neurons primarily targeted the hippocampus, and the activation of these fibers reduced hippocampal seizure severity. By combining extracellular recording and pharmacological methods, we found that activating entorhinal CaMKIIα-positive neurons induced the GABA-mediated inhibition of hippocampal neurons. Optogenetic activation of focal hippocampal GABAergic neurons mimicked this neuronal modulatory effect and reduced hippocampal seizure severity, but the anti-epileptic effect is weaker than that of entorhinal LFES, which may be due to the limited spatial neuronal modulatory effect of focal photo-stimulation. Our results demonstrate a glutamatergic-GABAergic neuronal circuit for LFES treatment of epilepsy, which is mediated by entorhinal principal neurons.
| S-EPMC5161446 | biostudies-literature
Project description:Immunotherapy, represented by immune checkpoint inhibitors (mainly referring to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockades), derives durable remission and survival benefits for multiple tumor types including digestive system tumors [gastric cancer (GC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC)], particularly those with metastatic or recurrent lesions. Even so, not all patients would respond well to anti-programmed death-1/programmed death-ligand 1 agents (anti-PD-1/PD-L1) in gastrointestinal malignancies, suggesting the need for biomarkers to identify the responders and non-responders, as well as to predict the clinical outcomes. PD-L1expression has increasingly emerged as a potential biomarker when predicting the immunotherapy-based efficacy; but regrettably, PD-L1 alone is not sufficient to differentiate patients. Other molecules, such as tumor mutational burden (TMB), microsatellite instability (MSI), and circulating tumor DNA (ctDNA) as well, are involved in further explorations. Overall, there are not still no perfect or well-established biomarkers in immunotherapy for digestive system tumors at present as a result of the inherent limitations, especially for HCC. Standardizing and harmonizing the assessments of existing biomarkers, and meanwhile, switching to other novel biomarkers are presumably wise and feasible.
| S-EPMC7991593 | biostudies-literature
Project description:Our current understanding of human physiology and activities is largely derived from sparse and discrete individual clinical measurements. To achieve precise, proactive, and effective health management of an individual, longitudinal, and dense tracking of personal physiomes and activities is required, which is only feasible by utilizing wearable biosensors. As a pilot study, we implemented a cloud computing infrastructure to integrate wearable sensors, mobile computing, digital signal processing, and machine learning to improve early detection of seizure onsets in children. We recruited 99 children diagnosed with epilepsy and longitudinally tracked them at single-second resolution using a wearable wristband, and prospectively acquired more than one billion data points. This unique dataset offered us an opportunity to quantify physiological dynamics (e.g., heart rate, stress response) across age groups and to identify physiological irregularities upon epilepsy onset. The high-dimensional personal physiome and activity profiles displayed a clustering pattern anchored by patient age groups. These signatory patterns included strong age and sex-specific effects on varying circadian rhythms and stress responses across major childhood developmental stages. For each patient, we further compared the physiological and activity profiles associated with seizure onsets with the personal baseline and developed a machine learning framework to accurately capture these onset moments. The performance of this framework was further replicated in another independent patient cohort. We next referenced our predictions with the electroencephalogram (EEG) signals on selected patients and demonstrated that our approach could detect subtle seizures not recognized by humans and could detect seizures prior to clinical onset. Our work demonstrated the feasibility of a real-time mobile infrastructure in a clinical setting, which has the potential to be valuable in caring for epileptic patients. Extension of such a system has the potential to be leveraged as a health management device or longitudinal phenotyping tool in clinical cohort studies.
| S-EPMC9931296 | biostudies-literature