Research Vincent Van Rompaey

Abstract

Despite receiving little attention, vestibular disorders result in loss of vestibular (inner ear) function and create costly health disparities. One-third of the population experiences some form of vestibular loss (VL) that presents with a mix of symptoms, from dizziness to brain fog, that reduces both quality of life and workforce capacity, and, for unknown reasons, is more prevalent and disabling in women. For most individuals with VL, the underlying etiology is unknown, and management is insufficient. Due to its prevalence, disability, and poor management, VL results in aggregated costs likely exceeding €6 billion per year in Europe. To combat the burden of VL and address the need for innovation along the entire chain, from basic knowledge to new treatments, we mobilize an international team of 13 academic and 9 non-academic partners who unite specialized scientific and clinical expertise, advances in computing, device engineering and remote management platforms, and clinical and patient networks. We synergize these resources to deliver state-of-the-art training necessary for 10 doctoral candidates (DCs) to innovate the new tools (knowledge, approaches, and devices) essential to understand the etiology of VL, capture and interpret (characterize) the relevant symptoms of VL, and expand treatments to restore vestibular function. With collaborative impact activities, we additionally train DCs to enable diverse end users to adopt, use, and further innovate these tools and stakeholders to better advocate for future innovation. By training new leading experts, we aim to advance patient-centered care of VL and, moreover, reduce healthcare costs and promote sustainable "green" healthcare systems while also enhancing workforce and innovation capacity for individuals with VL and in the emerging academic, clinical, and industrial sectors focused on the care of VL. PROVIDE will be a model for future networks tackling challenges in healthcare and striving for health equity.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Chronic otitis media refers to a group of complex infectious and inflammatory diseases of the middle ear, causing permanent tympanic membrane perforations and conductive hearing impairment. Tympanoplasty and myringoplasty are commonly used surgeries to eradicate the disease and to reconstruct the eardrum. However, both strategies are associated with drawbacks including recurrent perforations, high capital investment, time-consuming quality control and limited availability of autologous graft tissue. A possible solution to address these issues is offered by the field of tissue engineering (TE). Although significant progress has been realized, there remain shortcomings related to current TE approaches including the lack of sufficient tympanic native tissue mimicry in terms of mechanical and morphological complexity. The aim of the current PhD research thus includes: (1) the development of 'clickable' poly-?-caprolactone- and gelatin-based building blocks containing photopolymerizable groups which can be applied as starting materials for the fabrication of 3D printed eardrums; (2) additive manufacturing of the 'clickable' building blocks via digital light processing and two-photon polymerization towards the creation of 3D printed eardrums; (3) in-depth characterization of the 3D printed constructs resulting in a profound understanding of the scaffolds' properties; (4) in vitro, in vivo and ex vivo evaluation of the artificial eardrums focusing on performance.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss has a significant impact on quality of life and cognitive function, affecting more than 1.57 billion people worldwide. The application will focus on the autosomal dominant disorder DFNA9 which leads to post-lingual severe-to-profound sensorineural hearing loss (SNHL). DFNA9 is caused by heterozygous mutations in the COCH gene that lead to the formation of mutant cochlin. Currently, no treatment is available to prevent or cure SNHL in DFNA9. This application presents an innovative approach to go beyond the current state-of-art in the field of SNHL by in vivo evaluation of a disease-modifying gene therapy injected in the inner ear to downregulate expression of the mutant COCH allele. The applicant will do so by using lipid nanoparticles loaded with a CRISPR-nuclease optimized in vitro in a unique genetically humanized DFNA9 mouse model carrying the exact mutation of our human population. By sparing the normal allele, a heterozygous protein-truncating mutation will be created, which would not lead to a phenotype of SNHL. The application also presents an innovative approach to identify tissue-specific (perilymph) and blood-based bio-assays in humans and mice, that reflect tissue-specific pathophysiology only available in the mouse model. The discovery of these in vivo biomarkers will be a major breakthrough in the SNHL field and important to evaluate future disease-modifying therapies for DFNA9 at a molecular and biochemical level.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Fellow: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss has a significant impact on quality of life and cognitive function, affecting more than 1.57 billion people worldwide. The application will focus on the autosomal dominant disorder DFNA9 which leads to post-lingual severe-to-profound sensorineural hearing loss (SNHL). DFNA9 is caused by heterozygous mutations in the COCH gene that lead to the formation of mutant cochlin. Currently, no treatment is available to prevent or cure SNHL in DFNA9. This application presents an innovative approach to go beyond the current state-of-art in the field of SNHL by in vivo evaluation of a disease-modifying gene therapy injected in the inner ear to downregulate expression of the mutant COCH allele. The lab will do so by using lipid nanoparticles loaded with a CRISPR-nuclease optimized in vitro in a unique genetically humanized DFNA9 mouse model carrying the exact mutation of our human population. By sparing the normal allele, a heterozygous protein-truncating mutation will be created, which would not lead to a phenotype of SNHL.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Verdoodt Dorien
• Fellow: Sels Lize

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss is the most frequently reported sensory deficit and affects 1.57 billion people worldwide. It has a significant impact on quality of life. Studies have identified a significant correlation between hearing status and cognitive abilities. Deafness Autosomal Dominant 9 (DFNA9) is a dominant hereditary disorder characterized by a progressive sensorineural hearing loss (SNHL) associated with bilateral vestibulopathy (BV). In this project, the applicant will evaluate hearing, vestibular and cognitive function in (pre-)symptomatic DFNA9 patients and in genetically humanized DFNA9 mice. Based on the statistical analysis of baseline (cross-sectional) data already gathered, the applicant hypothesizes that DFNA9 patients are at significant risk for incident cognitive decline. This application presents a novel approach to identify pathophysiological mechanisms of SNHL, BV and cognitive decline in a genetically engineered mouse model designed to mimic DFNA9 in humans. This model is unique in the field of hearing research and will allow us to investigate the therapeutic potential of any gene editing intervention intended for human use beyond the scope of this application. The expected outcome is important to society because it may identify DFNA9 patients at risk for cognitive decline. Subsequently, it will provide data from a genetically humanized mouse model essential to translate findings from fundamental research to clinically meaningful knowledge and clinical trials.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Van Dam Debby
• Fellow: Gommeren Hanne

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing impairment is a major disability affecting communication and quality of life. Speech perception tests are essential to measure the functional use of hearing, and to determine the effectiveness of hearing aids and implants. However, these language-based tests are influenced by linguistic and neurocognitive skills. So far, there are no objective tests to accurately predict hearing abilities and not require active participation. This is especially troublesome for patients with insufficient language proficiency, children or cognitive impairment. The project team has developed a non-attentive and objective prediction model which correlates very well with speech perception in noise scores. This model uses electroencephalography to measure brain activity alterations caused by frequency changes. In this project we aim to validate this Acoustic Change Complex (ACC) prediction model in a large-scale external validation study. In this project we will first optimize the recording procedure for efficient clinical use, and then perform a diagnostic test accuracy study in patients with varying degrees of sensorineural hearing loss, to confirm the high predictive value of the ACC model and to assess its test-retest reliability. If this project proves that the ACC prediction model is an effective and reliable biomarker of speech perception, it will finally give audiologists and doctors a hearing evaluation tool, to be used in a population who needs their hearing the most as they are already struggling with their communication. These patients and the general population will directly benefit from this diagnostic advancement, as it can increase the accuracy of their hearing evaluations and improve access to adequate hearing rehabilitation.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss (HL) is a growing problem in modern society, and is associated with an increased risk for social isolation and unemployment. Although the genetic basis of adult-onset HL is still largely elusive, heritability is suggested in 30-70% of cases. Lacking curative or preventive (genetic) treatments, hearing aids and cochlear implantation (CI) can relieve part of the burden of HL. However, the majority of patients with adult-onset HL still do not experience a satisfactory improvement of their auditory function with these devices. Furthermore, the outcome of CI in adult-onset cases is often less favorable as compared to CI in congenital HL cases. DFNA9, caused by mutations in the COCH gene, is amongst the best-studied forms of dominantly-inherited adult-onset HL. The c.151C>T (p.(P51S)) mutation likely occurred many generations ago, and is now estimated to cause adult-onset progressive HL and vestibular dysfunction in >1500 Dutch and Belgian individuals. The high prevalence of this founder mutation in our cohorts presents a unique opportunity to overcome the translational obstacles in the development of novel inner ear therapeutics. The adult onset of hearing loss provides a window of opportunity for therapeutic intervention. The large cohort of patients with the exact same mutation provide enough power for future clinical trials. The dominant inheritance pattern of DFNA9 implies that only one of the two gene copies (alleles) contains a mutation. These DFNA9 mutations in the COCH gene are all well-established to result in the production of toxic cochlin proteins that interfere with the function of the healthy cochlin proteins produced from the healthy allele. As such, a treatment that can block the formation of these toxic cochlin proteins has high therapeutic potential, especially when administered in an early stage of the disease. The remaining cochlin proteins produced from the healthy allele are sufficient for normal inner ear function. Recently published antisense oligonucleotides (AONs; small strands of synthetic DNA and RNA molecules) can specifically induce the degradation of c.151C>T mutant COCH transcripts, but not COCH transcripts resulting from the healthy allele (de Vrieze et al, Molecular Therapy – Nucleic Acids, 2021). In this project, we aim to further improve the efficiency and stability of our best-performing c.151C>T AON by introducing chemical modifications, and perform a series of pre-clinical validation studies in patient-derived stem cell models and a humanized DFNA9 mouse model. These data will provide a strong foundation for a swift translation of our AON treatment to future clinical trials. As there is virtually no prior art on the use of AONs to treat inner ear disorders, our studies are designed to also provide insights in the safety and feasibility of AONs a treatment paradigm of inner ear disorders in general.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by a heterozygous gain-of-function mutation in the COCH gene (Coagulation Factor C Homology) and is characterized by progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) and deafness. Within Belgium and the Netherlands, there are >1000 patients affected by the p.P51S COCH mutation, who – in the current absence of a disease modifying therapy – will develop deafness. A promising approach to tackle the pathophysiological mechanism of DFNA9 and stop or delay the onset of SNHL is to introduce a CRISPR-Cas9-based therapy into the inner ear, delivered by an AAV vector to disrupt or downregulate the expression of (mutant) COCH. In this project, I will phenotype a newly established humanized DFNA9 mouse model and assess whether in vivo delivery of a CRISPR-nuclease using an AAV-based viral vector leads to specific disruption of COCH.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Fellow: Verdoodt Dorien

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss affects 1.57 billion people worldwide and has been listed by the World Health Organisation as a priority disease for research into therapeutic interventions. DFNA9 is the most frequent hereditary disorder in Belgium and the Netherlands causing hearing loss at 20-30 years and evolving towards deafness by 60-70 years. Currently, there is no therapy available. The aim of this project is to develop a gene therapy that can delay or stop the progression of DFNA9 in the pre-symptomatic window of opportunity. Only one of the two copies of the COCH gene (one inherited from either parent), is mutated in DFNA9 and encodes for a toxic protein that affects the aging inner ear. Our therapeutic approach is designed to specifically stop the production of this mutated COCH protein, leaving the patient only with healthy COCH proteins. Earlier research has demonstrated that one healthy COCH gene is sufficient for normal hearing. It is of vital importance that protein production from the healthy COCH gene is not affected. As mutant and healthy COCH only differ by a single nucleotide, high sensitivity and specificity is essential to specifically recognize the mutant COCH gene. To achieve this, we will adapt the genetic manipulation tool "CRISPR-Cas9". This project will provide insight in which approach is most suitable to safely and specifically block the production of mutant COCH proteins and will lay the foundation for continued (pre)clinical development towards clinical trials.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project will identify previously unknown proteins in auditory hair cells and characterize their function. The outcomes will provide useful knowledge for the development of therapeutic approaches for hearing impairment. The auditory hair cells are found in the organ of Corti (in the inner ear). These cells are specialized sensory cells that transduce auditory signals into an electrical signal that is sent to the brain. Some of the proteins involved in auditory hair cell functioning are already identified by classical genetic approaches - via identification of causative genes in patients with hearing impairment or via mouse models. However, the majority of proteins involved in critical complexes for hearing remains unidentified. This project will identify new components of the lower tip-link complex in the organ of Corti with affinity purification (AP) followed by mass spectrometry (MS). The latest evolutions in proteomic techniques resulting in a gain in MS sensitivity now make this possible for the first time. Our preliminary data confirms the feasibility of this AP-MS approach for the hair cell complexes. New components will be identified and for a selection of these the molecular interactions with other proteins of the complex will be analysed in-depth. Additionally, we will identify the location of these proteins in the hair cells and their effect of ablation on hearing.

Researcher(s)

• Promoter: Baggerman Geert
• Promoter: Van Rompaey Vincent
• Co-promoter: Van Wielendaele Pieter

Research team(s)

• Translational Neurosciences (TNW)
• Ecosphere

Project type(s)

• Research Project

Abstract

Tinnitus is a common symptom that affects 10 to 15% of the adult population, causing mood changes, anxiety, depression, sleep disorders, concentration problems and other psychological/emotional issues leading to severe disruptions to the quality of life. Tinnitus does not represent a disease itself but instead is a symptom of a variety of possible underlying diseases or malfunctions making the tinnitus population very heterogeneous. In this project we address one specific subtype, being somatic tinnitus. In somatic tinnitus, the tinnitus is influenced by dysfunctions of the cervical spine and/or temporomandibular area, such as: increased muscle tension or mobility limitations. The content of the state-of-the-art therapy for somatic tinnitus is well established, but the implementation in clinical practice is not ideal yet. The current standard physiotherapy treatment, including manual mobilizations and exercises that are mostly performed at home, is perfectly implementable, but patients often do not perform home exercises or do them incorrectly. Furthermore, physiotherapists often lack knowledge about tinnitus in general, what makes it very hard for them to provide the correct tinnitus counselling that should be part of the somatic tinnitus therapy. To overcome these hurdles, a smartphone application was developed by the consortium partners, that provides tinnitus counselling through a chatbot function. The application also contains an exercise program, with daily reminders and videos to show how the exercises should be performed correctly. This application was tested by a panel of 30 tinnitus patients for user-friendliness and willingness-to-use, but the effectiveness of the application as part of a blended physiotherapy intervention still needs to be evaluated. Furthermore, our project aims to investigate the cost-effectiveness of this blended physiotherapy program compared to the current standard care.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

In many patients with an acute unilateral vestibular deafferentiation (uVD) syndrome symptoms are expected to resolve spontaneously because of central compensation. However, more detailed observations have revealed that 29-66 % of uVD patients develop disabling chronic dizziness lasting >1 year after the acute event. Identifying predictors of chronic dizziness would allow patients at high risk to be targeted with personalized therapies to reduce healthcare costs. Therefore, the main objective of this study is to identify predictors of chronic dizziness after an acute uVD. Despite the consensus on the usefulness of physical therapy, incorporation of physical therapy programs in daily management of patients after acute uVD remains troublesome. The approach usually consists of encouraging patients to move around as much as possible without the supervision of the physical therapist. However, there are no known studies that investigate exercise adherence in acute patients who rehabilitate based on home exercise programs. Therefore, the first objective is to study the effect of the actual level of physical activity in the acute stage on long term (LT) outcome. Recent data show that LT prognosis is more linked to anxiety and somatization traits than to objective vestibular findings. Avoiding complaint-inducing movements is a known compensation strategy used by patients with an acute uVD. However these movements are very important to promote compensation. Therefore, the second objective is to study the effect of activities avoidance behavior on LT outcome. As stated above it is questioned whether objective vestibular findings can predict chronicity. However recently the Perez and Rey (PR) score was developed. It is a measure of temporal organization of refixation saccades that enables to distinguish between compensated and uncompensated vestibular patients. Therefore, the third objective is to study the effect of early central vestibular compensation as measured by the PR score on LT outcome. In patients with poor central vestibular compensation the remaining sensory cues will need to compensate for the loss of vestibular information. Patients using a visual compensation strategy can become dependent of stable visual cues. Evidence is mounting that visual field dependency is a factor contributing to visual vertigo which is a specific form of persistent perceptual postural dizziness (PPPD) which is classified as a chronic functional vestibular disorder. Therefore, the fourth objective is to study the effect of visual motion sensitivity on LT outcome. A 2-year prospective cohort study will be performed to study aforementioned risk factors for chronic dizziness. Up to 200 consecutive patients with an acute uVD will be included. Triage at the emergency department is performed by neurologists and ENT clinicians. All patients will undergo a standard ENT evaluation for dizziness. Subsequently they will be treated by means of symptomatic treatment (antivertiginous drugs) and early start of vestibular rehabilitation. Patients will be seen by a physical therapist at all measurement sessions within the first three months. Chronic dizziness is indicated by a score >30 on the Dizziness Handicap Inventory (primary outcome) after 6 months. In addition, the criteria from the Barany society will be used to see whether patients suffer from PPPD (visual vertigo) or not. Possible risk factors will be evaluated by using MOX1-activity loggers (objective 1), the Vestibular Activities Avoidance Inventory (objective 2), video Head Impulse Testing including the Perez & Rey score (objective 3), Subjective Visual Vertical test and Rod & Disc test (objective 4). Measurements will be taken 1, 2, 3, 6, 9, 10, 26 and 52 weeks after the acute event. The risk factors will be used as predictors in a logistic regression model, that predicts whether a patient will have a DHI-score above or below 30. The predictive accuracy of the model will be assessed using ROC curves.

Researcher(s)

• Promoter: Vereeck Luc
• Co-promoter: Van Rompaey Vincent
• Fellow: Van Laer Lien

Research team(s)

• Movement Antwerp (MOVANT)

Project type(s)

• Research Project

Abstract

In this project, the main objective is to investigate the evolution of hearing levels and speech understanding in carriers of the P51S mutation in the COCH gene. This autosomal dominant disorder, known as DFNA9, is characterized by a progressive decline of hearing and vestibular function and will eventually lead to deafness and vestibular loss. No cure is currently available for DFNA9. The optimal therapeutic approach would be to prevent the onset of symptoms, e.g. by developing genetic therapies to target and block the mutation. Because longitudinal data on hearing function within this population are lacking, the applicant has already gathered prospective data to increase our understanding of its evolution. More specifically, the recently identified effect of sex on the natural evolution of hearing levels and speech understanding, and interaural differences will be studied using the complied dataset. These results will be essential for the design of future clinical trials studying disease-modifying therapies. Currently, DFNA9 patients can be rehabilitated with hearing aids and cochlear implants but this leads to a variable outcome with respect to speech understanding. For this reason, our third objective is to investigate the neural reserve in a cohort of cochlear implant users with DFNA9 by using electrically-evoked compound action potentials (ECAP's). By doing so, we will evaluate the responsiveness of the auditory nerve and measure the implications for speech perception.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss has a significant impact on quality of life and society in general. Hearing impairment is the most frequent sensory deficit in human populations, affecting 360 million people worldwide. It was listed by the World Health Organization as one of the priority diseases for research into therapeutic interventions to address public health needs. DFNA9 is a dominant hereditary disorder, caused by heterozygote mutations in the COCH gene, which progressively leads to bilateral deafness and balance loss by the age of 50-70 years. Currently, no treatment is available to prevent hearing loss or balance loss in DFNA9 patients. Local gene therapy to restore hearing or prevent hearing loss has been studied in neonatal mouse models for several years. Currently, a clinical study is ongoing in adult patients with profound hearing loss to restore hair cells by injecting virus-based vectors -carrying correcting genetic information- directly into the inner ear. In this project, we aim to generate an inner ear gene therapy tool to prevent hearing loss in a pre-clinical mouse model of DNFA9.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by a heterozygous gain-of-function mutation in the COCH gene (Coagulation Factor C Homology) and is characterized by progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) and deafness. At current, it is believed that the presence of aberrant COCH proteins in the extracellular matrix (ECM) of the inner ear leads to local cell damage resulting in progressive hearing loss. Within Belgium and the Netherlands, there are > 1000 patients affected by the P51S COCH mutation, who – in the current absence of a disease modifying therapy – will develop deafness and balance loss. Furthermore, there are over twenty different COCH mutations identified in people from all over the world that lead to SNHL. Given the genetic nature of this disorder with highly specific mutations, as well as recent advances in CRISPR-nuclease mediated gene therapeutic approaches, there is a great opportunity to develop a successful therapeutic strategy to reduce or prevent DFNA9-induced SNHL.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Camp Guy

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Aside from typical symptoms such as postural imbalance, vertigo, dizziness, nausea, and problems with gaze stabilization, patients with vestibular disorders (VD) often suffer from cognitive impairment (memory loss, loss of concentration, inability to multitask, fatigue, and headaches). On the one hand, these cognitive symptoms may be directly related to altered (e.g. hippocampal) vestibular projections throughout the brain, which are also involved in cognitive functions. On the other hand, these symptoms may be indirectly explained by difficulties in performing a motor and cognitive task simultaneously (dual-tasking), expressed by impaired cognitive-motor interference. The aim of the current study is to elucidate the impact of VD on cognitive and motor function, assessed in single and dual-task (DT) condition. Therefore, a test battery was developed and constructed based on a systematic review on psychometric properties of DTs in a variety of populations. The test protocol comprises five different cognitive tests, all assessing a different cognitive domain, which will be performed separately (single task) as well as during motor tasks (DT). This test protocol will be standardized in healthy controls, and subsequently validated in patients with bilateral vestibulopathy. The standardized and validated test protocol will then be performed in persons with unilateral vestibular loss. Finally, possible correlations between functional data and neuroimaging will be explored.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The world population has been aging dramatically, with 12% aged 60 years or older, and a rising number developing dementia. Yet, until now no cure or therapy to slow down the disease has been identified. Recent studies have established that hearing loss increases the risk for developing dementia. Because hearing loss can be treated with a hearing aid or cochlear implantation, this could potentially delay the onset of dementia. Many studies have reported improvement in cognition after hearing rehabilitation, but this might have been caused by just hearing the mostly verbal tests better. Many studies have demonstrated that balance organ function, located in the inner ear, also has an effect on cognition. However, while hearing loss and balance organ function loss often occur simultaneously, it has not been systematically evaluated in older adults. Our aim is to study the effect of hearing loss and balance organ function loss on learning and memory (i.e. cognition) in older subjects (55 years or older) and patients with mild cognitive impairment and Alzheimer's disease. We will do so by systematically evaluating hearing and vestibular function in these subjects, by using a cognitive assessment tool that is adapted to a potentially hearing impaired population, by using objective measurements of electrical activity in the auditory cortex evoked by sound and by analyzing MRI volume changes in relevant areas of the brain to detect who is at risk for developing cognitive impairment.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Cras Patrick
• Co-promoter: Mertens Griet
• Co-promoter: Van Ombergen Angelique

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss has a significant impact on quality of life and society in general. Hearing impairment is the most frequent sensory deficit in human populations, affecting 360 million people worldwide. It was listed by the World Health Organization as one of the priority diseases for research into therapeutic interventions to address public health needs. DFNA9 is a dominant hereditary disorder, caused by heterozygote mutations in the COCH gene, which progressively leads to bilateral deafness and balance loss by the age of 50-70 years. Currently, no treatment is available to prevent hearing loss or balance loss in DFNA9 patients. Local gene therapy to restore hearing or prevent hearing loss has been studied in neonatal mouse models for several years. Currently, a clinical study is ongoing in adult patients with profound hearing loss to restore hair cells by injecting virus-based vectors -carrying correcting genetic information- directly into the inner ear. In this project, we aim to generate an inner ear gene therapy tool to prevent hearing loss in a pre-clinical mouse model of DNFA9. Using Adeno-associated virus (AAV)-based vectors, we will apply CRISPR-Cpf1 genome engineering technology to target directly within in the cochlea Coch genomic DNA in a safe and effective way in order to disrupt expression of the mutant (and wild type) Coch protein before onset of disease. Hereby, we expect to reduce or prevent DNFA9-associated sensorineural hearing loss.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter
• Fellow: Verdoodt Dorien

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The current project proposes a randomized, placebo-controlled study comparing the effects of high-definition transcranial direct current stimulation (HD-tDCS) to a control (sham) group. HDtDCS neuromodulation is, in general, considered as a save intervention as it is a form of noninvasive brain modulation with no to relatively mild side effects. Up until now, a total of 31 studies evaluated the effects of tDCS on tinnitus reporting a variety of effects ranging from no effects to significant tinnitus reduction. The present protocol proposes a randomized controlled trial comparing the effects of HD-tDCS therapy taking into account confounding factors such as age, gender, anxiety, depression and hearing loss (which are often not considered in previous studies). In this context, the proposed clinical trial will be the first high-quality powered randomized controlled trial of its kind and the results would be much appreciated by the tinnitus community as stated by the TINNET work group (a European network for tinnitus research and management). In addition, cognitive aspects such as attention and memory will be evaluated by use of a cognitive test battery. It has been previously shown that tinnitus might have deteriorating effects on cognition but the outcomes remain speculative so far. As such, a thorough cognitive exam will be carried out as well as the measurement of cortical auditory evoked potentials (CAEPs). CAEPs are the neurophysiological correlate of auditory processing in the brain which can be measured. This provides a measure that can be taken into account in the study providing an objective evaluation of tinnitus burden and tinnitus alleviation before and after tinnitus therapy. In addition, these measurements can be linked to the cognitive performance of patients which has never been done before.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Van de Heyning Paul

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The human eardrum is a conically shaped thin membrane which separates the outer ear from the middle ear. It conducts sound vibrations from the external ear canal to the ossicles and protects the middle ear from infections. The 3D shape of the eardrum plays a crucial role in this process and any structural change to its topography is an important indicator for existing or impending pathology or hearing impairment. In previous work, I have demonstrated that 3D shape data of a cadaveric human eardrum can be obtained by using a modified clinical otoscope that simultaneously projects structured light patterns onto the eardrum and records them with a digital camera, placed at a relative angle to the projection axis. By employing a high-speed camera and by using parallel programming techniques, the digital processing pipeline is sufficiently fast to extract full-field surface shape deformations of a dye-coated eardrum in real-time. In the proposed research project, I will redesign both the optical imaging engine and the hardware setup of the otoscopic device to increase its imaging resolution when applied to uncoated eardrums. This way, the non-invasive imaging technique can be employed in the clinical setup and dynamic 3D eardrum shape data of living patients can be gathered for the first time. I will validate tympano-topography as a diagnostic tool in the ENT-office in the detection of early-stage middle ear inflammation, cholesteatoma and Eustachian tube (dys)functioning.

Researcher(s)

• Promoter: Dirckx Joris
• Co-promoter: Van Rompaey Vincent
• Fellow: Van der Jeught Sam

Research team(s)

• Biophysics and Biomedical Physics

Project type(s)

• Research Project

Abstract

DNFA9 is a cause of autosomal dominant (AD) non-syndromic late-onset sensorineural hearing loss (SNHL) associated with progressive bilateral vestibular failure (BVF). The age of SNHL onset varies depending on the mutation though the average onset age lies around 3rd-5th decade. It typically starts as downsloping of the audiogram at the age of onset and evolution towards deafness. DFNA9 is caused by mutations in the COCH gene (Coagulation Factor C Homology), which is located on chromosome 14q12-13 and encodes for a 550 amino acid protein, cochlin, which is expressed throughout the inner ear in spindle-shaped cells located along nerve fibers between the spiral ganglion and sensory epithelium. Over twenty mutations have been identified in regions, including North America, Japan, Australia, Korea, China and Belgium/Netherlands. Our objective is to establish an in vitro proof-of-principle for a gene therapeutic approach that targets mutant cochlin expression in the inner ear using Anc80L65AAV/CRISPR/Cas9-mediated gene editing. We hope to establish in vitro that this technique enables specific correction or downregulation of the mutant COCH gene in mammalian cell lines without modulating the normal COCH allele, which is still present in this heterozygous disorder. This work can provide proof-of-concept for in vivo studies in transgenic heterozygous COCH mice targeting the mutated COCH gene by means of an AAV.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project