Aldh inhibitor restores auditory function in a mouse model of human deafness.
Aldh inhibitor restores auditory function in a mouse model of human deafness.
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Aldh 抑制剂可恢复人类耳聋小鼠模型的听觉功能。
DOI：
10.1371/journal.pgen.1009040
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发表时间：
2020-09
期刊：
影响因子：
4.5
通讯作者：
Wan G
中科院分区：
文献类型：
--
作者：
Zhu GJ;Gong S;Ma DB;Tao T;He WQ;Zhang L;Wang F;Qian XY;Zhou H;Fan C;Wang P;Chen X;Zhao W;Sun J;Chen H;Wang Y;Gao X;Zuo J;Zhu MS;Gao X;Wan G
遗传性听力损失是一种常见的健康问题，目前尚无有效的治疗方法。由转录因子POU4F3突变引起的DFNA15是常染色体显性非综合征性耳聋的最常见形式之一。在这项研究中，我们建立了一种新的人类DFNA15耳聋小鼠模型，其Pou4f3基因突变（Pou4f3Δ）与DFNA15家族病例中发现的相同。Pou4f3（Δ/+）小鼠以与DFNA15患者相似的方式遭受进行性耳聋。Pou4f3（Δ/+）耳蜗的毛细胞表现出明显的立体纤毛和线粒体病变，外毛细胞明显缺失。Pou4f3（Δ/+）小鼠的听力和外毛细胞丧失的进展受到其他遗传和环境因素的显著改变。使用Pou4f3（-/+）杂合敲除小鼠，我们也发现DFNA15可能是由Pou4f3基因的单倍不足引起的。重要的是，醛脱氢酶（Aldh）和视黄酸受体抑制剂抑制视黄酸信号传导，促进了耳蜗组织中Pou4f3的表达，抑制了突变小鼠听力损失的进展。这些数据表明，Pou4f3单倍性缺陷是人类DFNA15耳聋的主要潜在原因，并强调了Aldh抑制剂治疗进行性听力损失的治疗潜力。50%以上的耳聋病例是由于遗传缺陷而无法治疗。由转录因子POU4F3突变引起的DFNA15是常染色体显性非综合征性耳聋最常见的类型之一。在这里，我们建立了一种新的小鼠模型，与人类患者中发现的Pou4f3突变完全相同。突变小鼠表现出与人类患者相似的听觉病理生理，并表现出多种毛细胞异常。在小鼠模型中，听力损失的发生和严重程度是高度可改变的环境因素，如衰老，噪音暴露或遗传背景。通过一个新的敲除小鼠模型，我们发现Pou4f3单倍不足是人类DFNA15的潜在机制。重要的是，我们发现Aldh抑制剂是一种有效的小分子，可以上调Pou4f3并治疗突变小鼠的听力损失。鉴定用于治疗DFNA15耳聋的Aldh抑制剂代表了这种常见形式的进行性听力损失未满足的医疗需求的重大进展。
Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss. More than 50% of deafness cases are due to genetic defects with no treatment available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common types of autosomal dominant non-syndromic deafness. Here, we established a novel mouse model with the exact Pou4f3 mutation identified in human patients. The mutant mouse display similar auditory pathophysiology as human patients and exhibit multiple hair cell abnormalities. The onset and severity of hearing loss in the mouse model is highly modifiable to environmental factors, such as aging, noise exposure or genetic backgrounds. Using a new knockout mouse model, we found Pou4f3 haploinsufficiency as the underlying mechanism of human DFNA15. Importantly, we identified Aldh inhibitor as a potent small molecule for upregulation of Pou4f3 and treatment of hearing loss in the mutant mouse. The identification of Aldh inhibitor for treatment of DFNA15 deafness represents a major advance in the unmet medical need for this common form of progressive hearing loss.
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