Sarah Weckhuysen associate professor - fund. clinical researcher

Research Sarah Weckhuysen

Research team

Expertise

The focus of my research group is the elucidation of the molecular basis of genetic epilepsies. State-of-the-art genetic strategies resulted in the identification of several novel disease genes, such as de novo KCNQ2 mutations in neonatal epileptic encephalopathy. Using non-neuronal and iPSC derived neuronal cel models, we further study the effect of mutations on normal gene functioning. We have a close connection with the Neurology department at the UZA Hospital, where the PI is responsible for the epilepsy clinic. In the last years we have grown from a genetic research lab to a lab that works from bed (deep phenotyping of patients) to bench (genetic diagnosis and functional characterization) and back to bedside (therapeutic strategies).

Network-based computational drug repurposing for the treatment of KCNQ2-encephalopathy. 01/11/2024 - 31/10/2026

Abstract

Developmental and epileptic encephalopathy (DEE) caused by pathogenic variants in the KCNQ2 gene is a severe, early-onset neurological disorder characterised by neonatal seizures and developmental delay. Although seizures can be controlled in many KCNQ2-DEE patients with anti-seizure medication, there are no treatments that address the developmental problems. As a result, these children require intensive care for the rest of their lives. Given the slow and expensive nature of the drug discovery process, the prospects of providing safe and effective treatments for KCNQ2-DEE patients in a short term remain low. In this project, I will combine state-of-the-art in vitro brain organoids with transcriptomic technology, innovative electrophysiological readout systems and a computational prediction strategy to develop a drug screening platform to repurpose well-characterised FDA-approved drugs. This approach will provide unprecedented insight into the underlying molecular pathology of KCNQ2-DEE together with the potential to identify novel drug candidates for this disorder. If successful, the drug screening platform can be extended to other neurodevelopmental disorders for drug compound identification.

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  • Research Project

Increasing diagnostic yield in genetic childhood onset epilepsies through advanced multi-omics methods and improving mechanistic insights through the study of microglia-containing brain organoids. 01/10/2023 - 30/09/2028

Abstract

Monogenic childhood-onset epilepsy is associated with a high rate of therapy resistance and comorbid behavioral and neurodevelopmental problems. Accurate genetic diagnosis has been shown to inform precision medicine approaches and to improve outcome. For genetic epilepsies without available therapies, unraveling the underlying pathomechanisms can facilitate the identification of novel treatment targets, further improving adequate care for this patient group. We however remain unable to ascribe a molecular diagnosis to 2/3 of patients, and limited access to brain tissue of epilepsy patients complicates mechanistic studies. In this project, I will use two complimentary strategies to reduce the diagnostic gap and to increase knowledge of the disease mechanisms of genetic neurodevelopmental epilepsies. I will apply an advanced and integrated multi-omics pipeline on DNA and cell-free DNA of patients with severe childhood-onset epilepsy, and will develop a robust protocol for generation of microglia-containing human brain organoids. I will then use this model to study the disease mechanisms underlying KCNQ2 and KCNQ3 gain-of-function disorders, two genetic epileptic and neurodevelopmental disorders that are studied intensively by my group over the years, and that are thought to arise from the interaction between several brain cell types.

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  • Research Project

Electrophysiological and pharmacological characterization of human iPSC derived neuronal networks using a high-density microelectrode array. 01/10/2023 - 30/09/2026

Abstract

Pathogenic variants of KCNQ2 and KCNQ3 (KCNQ2/3) leads to a spectrum of disorders ranging from temporary neonatal seizures to epilepsy with lifelong severe intellectual disability. These genes encode voltage-gated potassium channels (Kv7.2/3) expressed in the central nervous system that regulate neuronal excitability. Over 190 variants have been identified, and channel function in non-neuronal heterologous systems has been described for the most clinically relevant of these variants. However, there is a knowledge gap between Kv7.2/3 dysfunction and the mechanisms by which they affect neurodevelopment. I propose to use human induced pluripotent stem cell-derived neurons carrying gain of function (GoF) and loss of function (LoF) KCNQ2/3 variants to test the hypothesis that pathogenic variants in KCNQ2/3 lead to aberrant neuronal network development. Using a state-of-the-art high-density microelectrode array (MEA), I will compare the electrophysiology between KCNQ2/3 variants in exclusively excitatory, and mixed excitatory:inhibitory neuronal networks. To test the ability of this in vitro MEA system for screening drugs, I will a) assess efficacy of channel activators and blockers and b) design novel antisense oligonucleotides as a targeted knockdown approach for GoF channelopathy. This proposal will provide a tunable system to study neurodevelopment, validate its potential for high-throughput drug screens, and develop lead compounds for treating Kv7.2/3 channelopathy.

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  • Research Project

Unraveling the role and contribution of neurons and microglia to the neurodevelopmental problems seen in children with KCNQ3 gain-of-function encephalopathy. 01/02/2023 - 31/01/2025

Abstract

Kv7.2 and Kv7.3 subunits, encoded by KCNQ2 and KCNQ3, form homo- or hetero-tetrameric voltage-gated potassium channels (Kv7 channel). Kv7 channels expressed in neurons produce a well characterized M-current that is a critical regulator of neuronal excitability by dampening repetitive firing. Gain-of-function (GoF) variants in KCNQ2 and KCNQ3 lead to severe early-onset neurodevelopmental disorders (KCNQ2- and KCNQ3-GoF-Encephalopathy). However, autism spectrum disorder (ASD) is a much more prominent feature in KCNQ3-GoF-Encephalopathy. This suggests for a Kv7.3 unique function during neurodevelopment. Interestingly, single nuclei RNA sequencing databases have revealed that KCNQ3 is the only KCNQ gene that is highly expressed in microglia in the human brain. Given the emerging evidence that microglia dysfunction is involved in the development of NDD and ASD, we hypothesize that KCNQ3-GoF variants affect microglia function which contributes to the already dysfunctional neuronal network. In this project, I will build a human tripartite neuronal-microglia model (excitatory neurons, inhibitory neurons and microglia) derived from induced pluripotent stem cells that carry KCNQ-GoF variants, as well as control lines. With this model I will (i) investigate the function of Kv7.3 in microglia and (ii) unravel the contribution of each cell type to KCNQ3-GoF-Encephalopthy. Furthermore, this model will be used as a screening platform to perform a proof-of-concept study for RNA interference using antisense oligonucleotides as a targeted treatment strategy for KCNQ3-GoF-Encephalopathy. When successful, this approach could be extended to other types of neurodevelopmental disorders and drug screenings.

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  • Research Project

Detection of somatic mutations and disease-defining methylation patterns in brain tissue and cerebrospinal fluid of patients with non-acquired focal epilepsy. 01/01/2023 - 31/12/2025

Abstract

Genetics is known to play a major role in patients with non-acquired epilepsy, and a genetic diagnosis enables more targeted treatment choices. However, two thirds of patients remain without a definitive genetic diagnosis. Studies ofresected brain tissue of individuals with focal epilepsy point towards an important role of pathogenic somatic variants and methylation abnormalities. Most epilepsy patients however do not undergo brain surgery, and the lack of brain tissue precludes a genetic and histopathological diagnosis. In this project, we aim to prove that cell-free DNA circulating in cerebrospinal fluid and serum of patients with focal epilepsy can be used to bridge this diagnostic gap. This project will establish and validate novel sequencing methods that in turn pave the way for better diagnosis, classification, and treatment for the large group of focal epilepsy patients who do not undergo epilepsy surgery.

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  • Research Project

Reducing onchocerciasis-associated morbidity in children. 01/11/2022 - 14/11/2025

Abstract

Onchocerciasis, caused by the parasite Onchocerca volvulus, is still endemic in Cameroon despite long-term annual community-directed treatment with ivermectin (CDTI). Low CDTI coverage and frequency (once a year) resulted in a high prevalence of onchocerciasis-associated morbidity (skin, eye, and neurological disease). Children infected with O. volvulus between the ages of 5-12 years are at risk of developing onchocerciasis-associated epilepsy. Moreover, O. volvulus infection during pregnancy induces "parasite tolerance" in the neonate and an increased risk to become infected with high parasitic loads, predisposing the child to develop onchocerciasis-associated morbidities. We hypothesize that maternal onchocerciasis has a negative impact on the neuro-cognitive development of the child. This will be investigated by recruiting nursing mothers with different exposures to onchocerciasis during pregnancy, and by monitoring the neurocognitive evolution of their children at 12 and 24 months of age. We also will evaluate a school-based ivermectin distribution strategy (adding to annual CDTI) to obtain six monthly intake of ivermectin by 5-12 year old children to prevent infection and ensuing morbidity. Understanding the impact of onchocerciasis on neurocognitive development during infancy and the possible benefits of an additional ivermectin dose in older children is expected to lead to interventions to preserve the intellectual capital of children in onchocerciasis-endemic regions.

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  • Research Project

A multi-omics approach to the detection of pathologic genetic and epigenetic lesions in Developmental and Epileptic Encephalopathies 01/01/2022 - 31/12/2025

Abstract

The Developmental and Epileptic Encephalopathies (DEE) are a group of rare and heterogeneous syndromes characterized by early-onset epilepsy with severe developmental delay, affecting approximately 1 in 2000 infants. In most patients, the cause is a high-impact genetic variant that often arises de novo, although recessive and X-linked inheritance also occurs. However, standard diagnostic practice involving whole-exome sequencing (WES) and chromosomal microarray can only detect pathogenic variants in 30-50% of the patients. We will use a complementary approach of long-read whole genome sequencing (LR-WGS) including methylome analysis and transcriptomics on fibroblasts of a cohort of 60 WES-negative DEE-patients to look for pathogenic events that can explain the remaining 50-70% of DEE cases. Our in-house experience with Nanopore LR-WGS will allow us to reliably detect structural genomic variants or repetitive elements causative in DEE. For a subset of these patients with novel pathologic changes, we will perform validation of our findings in neuronal tissue using our in-house experience in patient-sourced iPSC-derive neural cultures. Our multi-omics approach will allow us to correlate novel genetic and epigenetic lesions to specific disruptive effects on splicing and gene expression, thereby improving our ability to accurately detect true pathologic mechanisms. The results of this study will uncover novel disease mechanisms and improve our diagnostic accuracy.

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  • Research Project

Mutant allele silencing and novel potassium channel openers as targeted treatment strategies for KCNQ2 encephalopathy: validation in induced pluripotent stem cell derived neuronal cultures. 01/01/2021 - 31/12/2024

Abstract

KCNQ2-encephalopathy (KCNQ-E) is a severe epileptic disorder with onset in the first month of life, characterized by treatment resistant seizures and developmental delay. It is caused by mutations in the gene KCNQ2, encoding a type of potassium channel, that normally regulates brain excitability by acting as a "brake". Both a severe lack and excess of channel function can result in the development of KCNQ2-E. Seizures in children with KCNQ2-E often respond poorly to anti-epileptic drugs, and more importantly, therapies for the developmental problems are currently unavailable. In this project we will use patient derived neuronal cultures as a disease model to test safer and more potent analogues of retigabine, a drug that acts on KCNQ-channels but was recently withdrawn from the market due to side effects. In parallel, we will study the treatment potential of RNA interference, a biological process that can be exploited to reduce the expression of a disease-causing gene copy. Using this approach, we expect to provide pre-clinical evidence for two different types of targeted treatments that have the potential to improve the developmental outcome of KCNQ2-E.

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  • Research Project

Multidimensional analysis of the nervous system in health and disease (µNeuro). 01/01/2020 - 31/12/2025

Abstract

Neuropathological research is an interdisciplinary field, in which imaging and image-guided interventions have become indispensable. However, the rapid proliferation of ever-more inquisitive technologies and the different scales at which they operate have created a bottleneck at the level of integration, a) of the diverse image data sets, and b) of multimodal image information with omics-based and clinical repositories. To meet a growing demand for holistic interpretation of multi-scale (molecule, cell, organ(oid), organism) and multi-layered (imaging, omics, chemo-physical) information on (dys)function of the central and peripheral nervous system, we have conceived μNEURO, a consortium comprising eight established teams with complementary expertise in neurology, biomedical and microscopic imaging, electrophysiology, functional genomics and advanced data analysis. The goal of μNEURO is to expedite neuropathological research and identify pathogenic mechanisms in neurodevelopmental and -degenerative disorders (e.g., Alzheimer's Disease, epilepsy, Charcot-Marie-Tooth disease) on a cell-to-organism wide scale. Processing large spatiotemporally resolved image data sets and cross-correlating multimodal images with targeted perturbations takes center stage. Furthermore, inclusion of (pre)clinical teams will accelerate translation to a clinical setting and allow scrutinizing clinical cases with animal and cellular models. As knowledge-hub for neuro-oriented image-omics, μNEURO will foster advances for the University and community including i) novel insights in molecular pathways of nervous system disorders; ii) novel tools and models that facilitate comprehensive experimentation and integrative analysis; iii) improved translational pipeline for discovery and validation of novel biomarkers and therapeutic compounds; iv) improved visibility, collaboration and international weight fueling competitive advantage for large multi-partner research projects.

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  • Research Project

Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy into Adulthood. 19/04/2023 - 18/04/2024

Abstract

This is an award for the study resulting in the manuscript "Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood" published in Neurology 2022;99:e221-e233. doi:10.1212/WNL.0000000000200715

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  • Research Project

VIB-Assessing and quantifying gait problems in patients with STXBP1-related disorders using three-dimensional gait analysis. 01/02/2023 - 31/01/2024

Abstract

STXBP1-related disorder (STXBP1-RD) is a rare neurodevelopmental disorder caused by pathogenic variants in STXBP1. While initially described as characterized by seizures and intellectual disability (ID), the phenotypic spectrum considerably broadened and now includes ID without seizures, behavioral problems, and a range of movement disorders. To date, treatment is largely limited to seizure control. We recently showed that motor problems, including gait abnormalities, were present in 90% of adults with STXBP1-RD, contributing to the high level of functional dependence. Motor problems are complex, suggesting multisystem involvement. So far, no structured nor prospective examination of motor function has been performed in STXBP1-RD, and this is reflected by a lack of guidelines for motor revalidation of individuals with STXBP1-RD. In this project we aim to: (1) perform Instrumented 3D gait analysis in 30 patients (20 children and 10 adults) with STXBP1-RD (2) complement gait analyses with validated questionnaires focusing on functional mobility, structured clinical neurological examinations and EEG, (3) use the data acquired to characterize the gait disorders seen in STXBP1-RD, and develop guidelines for motor revalidation, and (4) define the optimal parameters for a prospective study that we subsequently will set up in a larger European cohort that we will establish within the European STXBP1 Consortium (ESCO). With several clinical trials investigating potential disease-modifying therapies for STXBP1-RD on the horizon, we are convinced that our study will greatly contribute to the identification of relevant and quantifiable non-seizure related endpoints related to motor function, a crucial step to ensure successful clinical trials.

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  • Research Project

Establishing neuroimmune brain organoids as a platform for neurodegenerative and neurodevelopmental disease research. 01/11/2022 - 31/10/2024

Abstract

Over the last decade, organoids emerged as an attractive middle ground between 2D cell cultures, which do not fully recapitulate the 3D environment and animal models, which pose technical and ethical limits. In particular, cerebral organoids are emerging as the next step in patient-derived in vitro models for both neurodevelopmental as well as neurodegenerative diseases. However, cerebral organoids have mostly been based on neuronal cells alone, while evidence increases that the role of non-neuronal types (microglia, astrocytes, endothelial cells) is critical in these conditions. Integration of these cell types will more closely mimic the in vivo cellular environment in health and disease and constitutes the major challenge of this project. The established neuroimmune organoid technology will find a wide range of applications as models for studying fundamental mechanisms underlying cellular biology and genetic pathophysiology as well as for efficient drug screening.

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  • Research Project

Comprehensive phenotyping of neuro-organoids by deep learning. 01/11/2022 - 31/10/2024

Abstract

Identification of disease mechanisms and novel therapeutic targets relies on the use of cell culture and animal models. While the former are overly simplified, the latter are not human and ethically contested. Suboptimal models at the discovery side will inevitably lead to a steep loss of leads in clinical trials. With the advent of human induced pluripotent stem cell technology, it has now become possible to generate organoids that more faithfully capture part of the heterogeneity and three-dimensional context of human tissue. Several research labs at the University of Antwerp (UA) recognize their potential and have therefore implemented a variety of human patient-derived organoid cultures, in particular for neuroscientific research lines. However, batch-to-batch variability and the inability to characterize these specimens at the cellular level with high-throughput, hamper their integration in a routine screening setting. Therefore, we have the ambition to develop an end-to-end solution that enables unbiased cellular phenotyping of intact neuro-organoids by using a combination of fluorescent labelling, advanced microscopy, and artificial intelligence (AI).

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  • Research Project

VIB-Pre-clinical imaging biomarkers of neurodevelopmental dysfunction in a mouse model of KCNQ2-developmental and epileptic encephalopathy. 02/01/2022 - 01/12/2024

Abstract

KCNQ2-developmental and epileptic encephalopathy (DEE) is a severe neurodevelopmental disorder, characterized by neonatal epilepsy and global neurological impairment. It is is one of the most common DEEs, caused by pathogenic variants in the gene KCNQ2, encoding a voltage-gated potassium channel subunit. No treatments are currently available that significantly impact neurodevelopment. In this project, we address the major hurdle in the development of new therapies: the absence of early quantifiable biomarkers of neurodevelopmental dysfunction (NDD). To reach this aim, we will use resting-state functional MRI (rs-fMRI) and positron emission tomography (PET) as non-invasive, in-vivo, longitudinal functional imaging techniques in wildtype mice and in an established mouse model of KCNQ2-DEE to identify pre-clinical biomarkers of NDD, because identification of alterations in functional connectivity using rs-fMRI and in synaptic density using PET imaging are believed to be promising biomarkers of cognitive function. We will then study the effect of the first precision therapy of KCNQ2-DEE, the potassium channel opener retigabine, on the established biomarkers in the same mouse model, and correlate this with its impact on cognitive performance at adult age. This research project will be the first in its kind to identify biomarkers of NDD, that can be used for future validation of new therapies in KCNQ2-DEE. Validation of the use of functional imaging in a rodent model of DEE would further provide the necessary pre-clinical evidence to justify studies in (young) human patients for subsequent translation to the clinical setting. If successful, our approach can be applied to other DEEs and neurodevelopmental disorders in general.

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  • Research Project

Targeted treatment for KCNQ related encephalopathies: retigabine analogues, repurposed drugs and allele specific knock down (TREATKCNQ). 01/04/2021 - 31/03/2024

Abstract

KCNQ-associated encephalopathies (KCNQ-E) are a group of severe epilepsies with onset in the first months of life, characterized by treatment resistant seizures and developmental delay. They are caused by mutations in genes encoding voltage-gated potassium channels that are responsible for the M-current, which plays a critical role in the regulation of neuronal excitability. Both a severe lack and excess of channel function can result in the development of KCNQ-E. Seizures in children with KCNQ-E often respond poorly to anti-epileptic drugs, and more importantly, therapies for the developmental problems are currently unavailable. With the aim to develop improved therapies for KCNQ-E, we will establish a consortium of researchers with expertise in KCNQ-related pathology and drug development, and access to a set of disease-relevant assays and models, such as fluorescence-based assays of potassium flux in cells, rodent and human neuronal cultures expressing KCNQ mutations, and mice modeling the characteristics of KCNQ-E. We will design and test safer and more potent analogues of retigabine, a drug that acts on KCNQ-channels but was recently withdrawn from the market due to side effects, and perform high-throughput drug screening to identify novel openers and blockers of KCNQ channels. In parallel, we will study the treatment potential of RNA interference using allele-specific antisense oligonucleotides, a biological process that can be exploited to reduce the expression of a disease-causing gene copy. We expect to provide pre-clinical evidence for different types of targeted treatments that have the potential to improve the developmental outcome of KCNQ-E.

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  • Research Project

The hidden genetics of Developmental and Epileptic Encephalopathies: a multi-omics approach. 01/10/2020 - 30/09/2024

Abstract

The Developmental and Epileptic Encephalopathies (DEE) are a group of clinically and etiologically heterogenous disorders that are characterised by early onset seizures and neurodevelopment delay. Most often they have a genetic origin, but although > 100 DEE genes are known to date, around 50% of children remain without diagnosis after performing whole exome sequencing (WES). We hypothesise that non-coding or synonymous genomic variants can have a disruptive effect on gene expression, not only through a direct effect on transcription, but also by influencing DNA methylation. By generating a complimentary dataset of genomics, transcriptomics and methylomics data on a cohort of well-characterised trio WES negative DEE patients, we will not only decrease the diagnostic gap in DEE, but will also contribute to our understanding of the impact of genomic variation on regulation of gene expression.

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Multi-well microelectrode array (MEA): a bridge to highthroughput electrophysiology. 01/05/2020 - 30/04/2024

Abstract

This project aims to upgrade the current electrophysiology technologies at UAntwerpen by acquiring a state-of-the-art MicroElectrode Array platform (MEA). To study the electrophysiological properties of excitable cells, currently patch-clamping is the gold standard. However, this is an extremely labour-intensive and invasive technique, limited to short-term measurements of individual cells at single time points. On the other hand, MEAs enable high-throughput non-invasive longitudinal real‐time measurements of functional cellular networks, without disrupting important cell-cell contacts, and thus provide a more physiologically relevant model. The multi-well format allows repeated recordings from cell cultures grown under various experimental conditions, including the opportunity to rapidly screen large drug libraries. Based on these advantages, multi-well MEAs are the most suitable instrument for functionally elucidating the pathomechanisms of neurological/cardiac disorders by performing (1) cardiac activity assays: measurement of field and action potentials from (iPSC-)cardiomyocytes to investigate wave-form, propagation and irregular beating; (2) neural activity assay based on three key measures: frequency of action potential firing, synchrony as measure for synaptic strength and oscillation as hallmark for neuronal organization in time; (3) (iPSC-)vascular smooth muscle contractility assay based on impedance alterations.

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Interactive and intelligent cellomics platform. 01/05/2020 - 30/04/2024

Abstract

Crucial insights in cell and developmental biology have been gained by virtue of live cell imaging technology. Along with a growing complexity of cellular models and the finesse with which they can be genetically engineered, comes a demand for more advanced microscopy. In brief, modern comprehensive cell systems research (cellomics) requires light-efficient, intelligent and interactive imaging modalities. To address this shared need, our consortium has identified a state-of-the art platform that allows ultrafast, yet minimally invasive imaging of small to medium-sized biological samples (from single cells to organoids) at high resolution, so as to capture dynamic events that range in timescale from voltage fluctuations to successive cell divisions. To only focus on those events that are truly of interest, and thereby boost throughput, the system is equipped with online image recognition capabilities. Finally, to allow targeted perturbations such as local damage induction or optogenetic switching, small regions can be selectively illuminated in the field of view. With this level of control, it will become possible to interrogate (sub-)cellular processes with unprecedented detail. The platform readily finds applications in diverse frontline research fields including neuroscience, cardiovascular research and infectious diseases, rendering it an indispensable asset for the applicants, the microscopy core facility and the University of Antwerp.

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Improving diagnostics and care for childhood onset epilepsies and its common neurological co-morbidities in Tanzania (Joint-COE). 01/01/2020 - 31/08/2022

Abstract

Childhood onset epilepsies (COE) are important causes of childhood morbidity in Sub-Saharan Africa (SSA), and are frequently accompanied by neurodevelopmental disabilities such as intellectual disability (ID). The treatment gap in SSA amounts to 80%, and stigma associated with both epilepsy and ID further increase disease burden for children and caregivers. Genetic factors are assumed to play a major role in COE, but access to genetic testing is non-existing in Tanzania. In this project we will 1) strengthen the research capacity on COE in Tanzania by establishing a research group supporting resident neurologists and PhD students in the development of research protocols addressing COE in Tanzania, and 2) improve quality of life of children with epilepsy (CWE) in Tanzania by a) improving diagnosis and care for CWE, by strengthen-ing medical education and local implementation of genetic testing; b) reducing the treatment gap by educa-tion of caregivers of CWE, c) improving access and quality of community-based rehabilitation programs

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Study and targeted treatment development for epileptic and encephalopathies using 2D and 3D human induced plupripotent stem cell-derived neuronal cultures. 01/01/2020 - 31/12/2020

Abstract

We will develop 2D and 3D hiPSC-derived neuronal cultures starting from patient material, as a model of epileptic encephalopathies (EE) such as KCNQ2-E, and perform multimodal characterization using electrophysiology and (high-content) microscopy. Comparison with neuronal cultures from control individuals and patients with milder forms of gene-related EEs, will enable us to differentiate epileptic and neurodevelopmental characteristics. We foresee that this will provide us much needed insight in the biological basis of the neurodevelopmental problems of the disorder. In a second step, we will contribute to the field of precision medicine for DEEs through a proof-of-concept study for mutant allele silencing as a treatment strategy for a selection of DEEs, using KCNQ2-E as a model disease. We will aim to revert the electrophysiological and morphological KCNQ2-E neuronal culture phenotype to the benign KCNQ2-B phenotype, using RNAi.

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Strengthening the Sfax University expertise for diagnosis and management of epilepctic encephalopathies (SEED). 01/10/2019 - 31/01/2023

Abstract

Epileptic encephalopathies (EE) are heterogeneous epilepsy syndromes associated with severe cognitive disturbance. EE vary in their age of onset, seizure types, electroencephalographic patterns and etiologies. New molecular technologies significantly increased the genetic diagnosis rate. In line with EU orientations and Twinning requirements, the SEED project will provide Sfax University (SU), with capacity building in excellence and innovation for earlier clinical and genetic diagnosis of EE, thanks to collaboration with Aix-Marseille University (AMU) and University of Antwerp (UA), two internationally leading organisations for the diagnosis of EE. Early clinical and genetic diagnosis allows more targeted early management, improves prognosis and thereby reduces health costs. The SEED project will: 1) strengthen the medical and technological capacity of SU in the use of innovative technologies of SU in the field of EE 2) allow access to scientific excellence at international level for members of the SU which will ultimately lead to a better integration into international networks in MENA and EU regions. The successful implementation of this strategy will rely on specific actions including: 1) enhancement of the existing and the creation of new innovative scientific and technical collaborations through short-term staff exchanges and short-term on-site training activities; 2) training of young researchers from SU to become trainers; 3) creation of an experts' network for EE management centered at SU; 4) increasing of awareness among the patients' families through targeted dissemination and communication activities and 5) development of a strategy to sustain network activity beyond the project deadline. Through the completion of these activities, and with the support of AMU and UA, SU will be able to significantly reduce networking gaps, to increase its ability to compete for international research funds and to link further with stakeholders. In addition, thanks to the SEED project, SU will become the reference center for the clinic and genetic diagnosis of EE in the MENA region.

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The silence of the mutant: towards a targeted therapy for KCNQ2-encephalopathy. 01/01/2019 - 31/12/2022

Abstract

KCNQ2-encephalopathy (KCNQ2-E) is a subtype of severe epilepsy, characterized by neonatal seizures and a severe developmental impairment. The disorder is caused by mutations in KCNQ2. As in other epileptic encephalopathies (EEs), all currently available treatments purely target seizures, whereas the neurodevelopmental outcome is at least as devastating for the quality of life. There is thus a strong need for new therapies that target both aspects of the disease. We will perform an in vitro proof of concept study for RNA interference as a targeted treatment strategy for KCNQ2-E, using 2D neuronal cultures derived from human induced pluripotent stem cells (hiPSC), in which we aim to tackle both disease components. Since KCNQ2-E is proven to be caused by dominant-negative or gain-of-function variants, and KCNQ2-haploinsufficiency is known to cause a self-limiting neonatal epilepsy with normal development (Benign Familial Neonatal Epilepsy (KCNQ2-B)), mutant allele specific silencing seems a promising treatment approach. Using mutant specific short hairpin RNAs, we aim to revert the electrophysiological KCNQ2-E neuronal culture phenotype to the benign KCNQ2-B phenotype. In parallel, we will generate brain organoids to more precisely model and study the neurodevelopmental process and deficits in KCNQ2-E, and provide a more advanced screening model for future treatments. When successful, this approach could be extended to many other EEs with similar mutation characteristics.

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  • Research Project

Allele-specific silencing of mutant KCNQ2 as a targeted treatment for KCNQ2 encephalopathy: an in vitro proof of concept study. 01/10/2018 - 30/09/2023

Abstract

Epilepsy is the forth most common neurological disorder, affecting around 50 million of people worldwide. The epileptic encephalopathies (EEs) are a heterogeneous subgroup of severe epilepsies with onset in the first years of life, which are characterized by treatment resistant seizures and developmental slowing or regression. The majority of EEs have a monogenic basis, and recent advances in gene discovery have greatly increased our neurobiological insights in these disorders. KCNQ2 encephalopathy, caused by mutations in the gene KCNQ2 as described in our research group, is the prototype and most frequent form of EE with neonatal onset. Seizures in these patients often respond poorly to the available anti-epileptic drugs, and more importantly, therapies targeting the neurodevelopmental problems are currently unavailable. In this project we aim to provide evidence for a targeted treatment strategy that has the potential to improve the developmental outcome of these patients. Using neuronal cultures derived of blood cells from patients with KCNQ2 encephalopathy as a disease model, we will study the treatment potential of RNA interference, a biological process that can be exploited to reduce the expression of a disease causing allele. Doing so, we aim to reverse both the epileptic and neurodevelopmental features of EEs. If successful, such an approach can be extended to many more EEs with similar characteristics.

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Studying the mechanisms of developmental delay in KCNQ2 encephalopathy using patient derived brain organoids. 01/10/2018 - 30/09/2022

Abstract

Epilepsy is one of the most common neurological disorders, characterized by spontaneous recurrent seizures. KCNQ2 encephalopathy (KCNQ2-E) is a severe subtype of epilepsy, characterized by seizures that appear in the first weeks of life, and a severe developmental delay for which no cure is available. The disorder is caused by a mutation in the KCNQ2 gene, encoding a potassium channel in the brain that is very important for the communication and development of neurons. In this project we will study the cause of the developmental problems of KCNQ2-E, since this is so far not understood, and seems to be at least partially independent from seizure activity. As a model we will use brain organoids, which are 3D structures derived from patient's pluripotent stem cells that represent the fetal brain in vitro. Brain organoids are a good model voor our project, because of the more complex cell interactions compared to 2D cultures. They can also generate human brain structures that are absent in animal models. The forebrain organoids will be characterizedmorphologically and electrophysiologically and compared to control organoids, with the eventual aim to understand the mechanisms underlying the developmental delay and to develop a potent read-out system for future therapeutic studies.

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  • Research Project

VIB-Sophies Award for Young KCNQ2 investigators. 22/06/2018 - 31/12/2018

Abstract

KCNQ2 encephalopathy is a severe neonatal epilepsy syndrome accompanied by intellectual disability. The disorder is caused by de novo mutations in a gene encoding for a voltage gated potassium channel subunit, KCNQ2. Seizures occur very frequent, and even if they can be controlled by anti-epileptic drugs, children are left with severe developmental problems. This prize was offered by the KCNQ2 encephalopathy patient organisation, to elucidate the pathomechanisms underlying this severe disorder, with the aim to develop better therapies.

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  • Research Project

Identification of novel disease genes in rare sib pairs with epileptic encephalopathies. 01/04/2018 - 31/03/2019

Abstract

Epilepsy is the fourth most common neurological disorder, affecting around 50 million of people worldwide. While 70% of individuals with epilepsy respond well to currently available anti-epileptic drugs, one third of people continues to present seizures despite multiple drug trials. Understanding the underlying causes and mechanisms of epilepsy is an important step for the development of novel treatments. The epileptic encephalopathies (EEs) are a heterogeneous subgroup of severe epilepsies with onset in the first years of life, which are characterized by treatment resistant seizures and developmental slowing or regression. The majority of EEs have a monogenic basis, and recent advances in gene discovery have greatly increased our neurobiological insights in these disorders. Nevertheless, the genetic cause of around 60-70% of EEs still remains unknown. In this project, we will conduct whole exome sequencing on a collection of very rare affected sib pairs with EEs in which mutations in known genes have been excluded previously. We thus will uncover novel genes for EE, improve diagnostics, and increase our understanding of the mechanisms leading to the disease. This is indispensable for future novel targeted treatment development, a much needed task for these severe disorders that are highly drug resistant.

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  • Research Project

Multi-disciplinary approach to control onchocersiasis-associated epilepsy in the Mahenge area in Morogoro region, Tanzania. 01/01/2018 - 31/08/2022

Abstract

Despite the use of ivermectin (IVM) once annually for control of onchocerciasis (oncho) (= river blindness) in Mahenge Tanzania, the prevalence of oncho and epilepsy remains high. There is increasing evidence that epilepsy is a complication of oncho and that treatment of oncho can not only eliminate blindness but also reduce epilepsy. Our proposed project aims to: 1) strengthen the multi-disciplinary research capacity for the prevention of oncho and epilepsy in Tanzania. We will establish an oncho-associated epilepsy (OAE) research group to support a master and a PhD-level student in the development of research protocols addressing OAE in the Mahenge region; 2) reduce the prevalence of oncho and the incidence of epilepsy in the Mahenge area by: a) establishing a surveillance system for early diagnosis of epilepsy; b) strengthening and implementing an effective community distribution of IVM; 3) Implement evidence-based guidelines to treat OAE by training local health care workers; 4) introduce community advocacy on epilepsy, epilepsy-associated stigma and discrimination.

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  • Research Project