Towards precision audiology for age-related hearing loss – PRESAGE

Age-related hearing loss (ARHL) is the most common sensory disease ranking among the top five in the global burden of disease study with considerable negative impact for the persons affected and considerable costs for the society. If not detected and treated early on (e?g. with hearing aids), it increases the risk for a faster progression of cognitive decline. Unfortunately, the rehabilitation success with hearing aids is still limited due to our restricted understanding of the complexity of ARHL pathophysiology, the variety of its defective sensory and neural mechanisms and due to their not well-understood perceptual consequences in the individual person. Hence, an in-depth understanding of the individual pathophysiology and the resulting individual sound processing deficits (phenotypisation) should be achieved in relation to the individual genotype as a prerequisite for a precise diagnostic and rehabilitation strategy including gene therapy.
PRESAGE addresses ARHL in a comprehensive way by exploring its genotype-phenotype relation in a carefully selected group of French and German patients. A precise diagnosis will be based on an advanced, model-guided phenotyping approach combining physiologic and psychoacoustic tests. This will be related to recent progress in genotyping of untimely ARHL (uARHL), defined as a decrease in hearing capability 20 years earlier than average (about 7% of ageing subjects). Since a monogenic heredity was found in 25% of uARHL cases, a genetically anchored strategy will be followed based on previous work in animal models, indicating a strong genotype-phenotype relation among the 35 genes already identified. Many of these encode proteins expressed only in one functional module of the auditory system, i?e., a cell or a subcellular structure, with a distinctive role in the processing of sound. This is expected to provide us with the unique opportunity to establish a straightforward causal relationship between the numerous pathogenic variants in our patients that induce a loss of function and the resulting electrophysiological and functional consequences found in their respective phenotypes.
PRESAGE associates two interdisciplinary groups of leading experts in fundamental and translational hearing research at the Institut de l'Audition in Paris, France (a center of Institut Pasteur) and the Cluster of Excellence Hearing4All, in Oldenburg, Germany. One strength of this consortium is the ability to recruit a group of appropriate subjects exhibiting uARHL – as shown by a clinical test battery – in combination with an appropriate genotype by drawing from a sufficiently large clinical population. The genetic dissection of uARHL in selected subjects will be combined with an extensive, common audiological test battery for phenotyping which is based on previous work and expertise from both partners. This will allow for a model-based analysis of the main perceptive consequences of monogenic uARHL within a clear-cut physiological framework. The model developed by the partners will first be validated with these genetically well-defined cases. It will then be applied to predict the phenotype of more complex pathogenic variants with more complex patterns in the loss of functions that result from the combination of deficits in several functional modules.
PRESAGE will not only establish a mechanistic rationale for diagnosing one type of ARHL for the first time with evidence-based recommendations for proper diagnostic tools. It will also determine if the monogenic cases of uARHL might be eligible for tailored compensation strategies, e?g. with specific hearing devices. Moreover, the project will serve as a pilot study with the long-term aim of identifying cases of ARHL as candidates to genuine targeted therapies (e?g., gene therapy). The applicants are convinced that PRESAGE will yield unforeseen perspectives for treating age-related hearing loss, thus alleviating the global burden of this disease.