Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA.
Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR, 97239, USA.
Hear Res. 2020 Sep 1;394:107931. doi: 10.1016/j.heares.2020.107931. Epub 2020 Mar 5.
Disabling hearing loss is expected to affect over 900 million people worldwide by 2050. The World Health Organization estimates that the annual economic impact of hearing loss globally is US$ 750 billion. The inability to hear may complicate effective interpersonal communication and negatively impact personal and professional relationships. Recent advances in the genetic diagnosis of inner ear disease have keenly focused attention on strategies to restore hearing and balance in individuals with defined gene mutations. Mouse models of human hearing loss serve as the primary approach to test gene therapies and pharmacotherapies. The goal of this review is to articulate the rationale for fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. The differential onset of hearing in mice and humans suggests that a prenatal window of therapeutic efficacy in humans may be optimal to restore sensory function. Mouse studies demonstrating the utility of early fetal intervention in the inner ear show promise. We focus on the modulation of gene expression through two strategies that have successfully treated deafness in animal models and have had clinical success for other conditions in humans: gene replacement and antisense oligonucleotide-mediated modulation of gene expression. The recent establishment of effective therapies targeting the juvenile and adult mouse provide informative counterexamples where intervention in the maturing and fully functional mouse inner ear may be effective. Distillation of the current literature leads to the conclusion that novel therapeutic strategies to treat genetic deafness and imbalance will soon translate to clinical trials.
到 2050 年，预计全球将有超过 9 亿人失聪。世界卫生组织估计，全球听力损失的年经济影响为 7500 亿美元。无法听到声音可能会使有效的人际交流变得复杂，并对个人和职业关系产生负面影响。内耳疾病的基因诊断的最新进展使人们强烈关注针对具有明确基因突变的个体恢复听力和平衡的策略。人类听力损失的小鼠模型是测试基因治疗和药物治疗的主要方法。本综述的目的是阐明用于治疗先天性听力损失和前庭功能障碍的胎儿基因治疗和药物治疗的基本原理。小鼠和人类听力的不同发病时间表明，人类可能存在治疗效果的产前窗口期，以恢复感觉功能。证明早期胎儿干预内耳的小鼠研究有希望。我们专注于通过两种策略来调节基因表达，这两种策略已成功治疗了动物模型中的耳聋，并在人类的其他疾病中取得了临床成功：基因替换和反义寡核苷酸介导的基因表达调节。最近针对幼年和成年小鼠的有效治疗方法的建立提供了有意义的反例，表明在成熟和功能齐全的小鼠内耳中进行干预可能是有效的。对当前文献的提炼得出结论，治疗遗传性耳聋和失衡的新治疗策略将很快转化为临床试验。
