PRESAGE: Towards PREciSion audiology for AGE-related hearing loss

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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 and 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 French and German patients. A precise phenotypisation will be based on advanced, model-guided physiologic and psychoacoustic tests. This will be linked to recent genotyping of untimely ARHL (uARHL), defined as a decrease in hearing capability 20 years earlier than average (about 7% of ageing subjects). A genetically anchored strategy will be followed based on previous work indicating a strong genotype-phenotype relation among the 35 genes already identified. Many of these encode proteins 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 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/ Institut Pasteur in Paris, France, and the Cluster of Excellence Hearing4All, in Oldenburg, Germany. A group of appropriate subjects exhibiting uARHL – as shown by a clinical test battery – in combination with an appropriate genotype will be selected from a sufficiently large clinical population. The genetic dissection of uARHL will be combined with an extensive audiological test battery for phenotyping which is based on 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 genetically well-defined cases and then applied to more complex pathogenic variants that result from the combination of deficits in several functional modules.The long-term aim is to identify cases of ARHL as candidates to genuine targeted therapies (e.g., better fitted hearing devices and, ultimatively, gene therapy), thus alleviating the global burden of ARHL.