Research team

Translational Neurosciences (TNW)

Expertise

Transgenic animal models for hereditary hearing loss and vestibular failure (DFNA9, COCH). Animal models for acquired hearing loss and vestibular failure. Measuring hearing by auditory brainstem recording, startle-reflex and distortion product oto-acoustic emissions. Measuring attention and tinnitus by prepulse-inhibition. Measuring balance by means of behavioral and reflex testing. Clinical audiovestibular evaluation/ Cognitive evaluation by means of the RBANS-H. Spatial navigation by means of the virtual Morris Water Task. Evaluation of tinnitus. Robotic-assisted cochlear implantation. Menière’s disease and bilateral vestibulopathy.

Development of allele-specific crispr-nuclease gene therapy for late-onset sensorineural hearing impairment in a humanized dfna9 mouse model. 01/01/2022 - 31/12/2025

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)

Research team(s)

Project type(s)

  • Research Project

Cost-effectiveness of a smartphone Application for Tinnitus Treatment: The CATT trial 01/10/2021 - 30/09/2025

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)

Research team(s)

Project type(s)

  • Research Project

Unravelling risk factors for chronic dizziness in patients after an acute unilateral vestibular deafferentiation syndrome. 01/10/2020 - 30/09/2024

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)

Research team(s)

Project type(s)

  • Research Project

The impact of a vestibular dysfunction on cognitive and motor performance in adults in single and dual-task condition. 01/11/2019 - 30/10/2023

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)

Research team(s)

Project type(s)

  • Research Project

Effect of hearing loss and vestibular decline on cognitive function in older subjects: correlation with cortical auditory evoked potentials and mri brain volume changes. 01/01/2019 - 31/12/2022

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)

Research team(s)

Project type(s)

  • Research Project

Inner ear gene therapy to prevent deafness in DFNA9. 01/10/2018 - 30/09/2022

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)

Research team(s)

Project type(s)

  • Research Project

A comparative, randomized trial on HD-tDCS and sham control group: effects on tinnitus severity and cognition including objective measures. 01/10/2018 - 30/09/2022

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)

Research team(s)

Project type(s)

  • Research Project

Research on gene therapy to cure hearing loss. 01/01/2020 - 31/12/2021

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)

Research team(s)

Project type(s)

  • Research Project

Development of allele-specific CRISPR-nuclease gene therapy for late-onset sensorineural hearing impairment in a new humanized DFNA9 mouse model. 01/01/2020 - 31/12/2020

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)

Research team(s)

Project type(s)

  • Research Project

Otoscopic profilometry: a new optical technique to quantitatively measure human eardrum deformation in-vivo, in 3D and in real-time. 01/10/2018 - 30/09/2021

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)

Research team(s)

Project type(s)

  • Research Project

Gene Therapy for DFNA9 : downregulating the mutant COCH gene in mammalian cell lines by uising a synthetic adeno-associated viral vector Anc80L65 and CRISPR/Cas9-mediated genetic editing. 01/11/2017 - 31/10/2018

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)

Research team(s)

Project type(s)

  • Research Project