PRESAGE: Towards PREciSion audiology for AGE-related hearing loss

年龄相关性听力损失(ARHL)是最常见的感觉性疾病，在全球疾病负担研究中排名前五，给社会带来了相当大的负面影响和代价。如果不及早发现和治疗(例如使用助听器)，它会增加认知功能下降更快进展的风险。不幸的是，由于我们对ARHL病理生理学的复杂性、其有缺陷的感觉和神经机制的多样性以及由于其在个体中的感知后果还没有很好地理解，助听器的康复成功仍然是有限的。因此，应该深入了解个体的病理生理学和由此导致的个体声音处理缺陷(表型)，作为包括基因治疗在内的精确诊断和康复策略的先决条件。PRESAGE通过探索法国和德国患者的ARHL的基因-表型关系来全面解决ARHL。精确的表型鉴定将基于先进的、模型指导的生理学和心理声学测试。这将与最近不合时宜的ARHL(UARHL)的基因分型有关，uARHL的定义是听力下降的时间比平均水平早20年(约7%的老年受试者)。在之前工作的基础上，将遵循遗传锚定策略，表明已识别的35个基因之间存在强烈的基因型-表型关系。其中许多编码的蛋白质在声音的处理中起着独特的作用。这有望为我们提供一个独特的机会，在我们的患者中导致功能丧失的众多致病变异与其各自表型中发现的后果之间建立直接的因果关系。PRESAGE与法国巴黎的L听力研究所/巴斯德研究所和德国奥尔登堡的卓越听力研究所的两个由基础和翻译听力研究领域的领先专家组成的跨学科小组合作。将从足够大的临床人群中选择一组表现为uARHL的适当受试者--如临床测试组合所示--并结合适当的基因型别。UARHL的基因解剖将与基于双方专业知识的广泛的表型表型听力学测试组合相结合。这将允许在明确的生理框架内对单基因uARHL的主要可感知后果进行基于模型的分析。合作伙伴开发的模型将首先用基因定义明确的病例进行验证，然后应用于由几个功能模块的缺陷组合而成的更复杂的致病变异。长期目标是确定ARHL病例是真正靶向治疗的候选病例(例如，更适合的听力设备，最终是基因疗法)，从而减轻ARHL的全球负担。

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.