Crowson Matthew Gordon, Hertzano Ronna, Tucci Debara L
*Division of Head & Neck Surgery and Communication Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina †Department of Otorhinolaryngology-Head & Neck Surgery, Anatomy and Neurobiology and Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland.
Otol Neurotol. 2017 Jul;38(6):792-803. doi: 10.1097/MAO.0000000000001427.
To critically review and evaluate the proposed mechanisms and documented results of the therapeutics currently in active clinical drug trials for the treatment of sensorineural hearing loss.
US National Institutes of Health (NIH) Clinical Trials registry, MEDLINE/PubMed.
STUDY SELECTION & DATA EXTRACTION: A review of the NIH Clinical Trials registry identified candidate hearing loss therapies, and supporting publications were acquired from MEDLINE/PubMed. Proof-of-concept, therapeutic mechanisms, and clinical outcomes were critically appraised.
Twenty-two active clinical drug trials registered in the United States were identified, and six potentially therapeutic molecules were reviewed. Of the six molecules reviewed, four comprised mechanisms pertaining to mitigating oxidative stress pathways that presumably lead to inner ear cell death. One remaining therapy sought to manipulate the cell death cascade, and the last remaining therapy was a novel cell replacement therapy approach to introduce a transcription factor that promotes hair cell regeneration.
A common theme in recent clinical trials registered in the United States appears to be the targeting of cell death pathways and influence of oxidant stressors on cochlear sensory neuroepithelium. In addition, a virus-delivered cell replacement therapy would be the first of its kind should it prove safe and efficacious. Significant challenges for bringing these bench-to-bedside therapies to market remain. It is never assured that results in non-human animal models translate to effective therapies in the setting of human biology. Moreover, as additional processes are described in association with hearing loss, such as an immune response and loss of synaptic contacts, additional pathways for targeting become available.
严格审查和评估目前正在进行的治疗感音神经性听力损失的临床药物试验所提出的机制和已记录的结果。
美国国立卫生研究院（NIH）临床试验注册库、MEDLINE/PubMed。
对NIH临床试验注册库进行检索，确定了候选听力损失治疗方法，并从MEDLINE/PubMed获取了相关支持性文献。对概念验证、治疗机制和临床结果进行了严格评估。
确定了在美国注册的22项正在进行的临床药物试验，并对6种潜在的治疗分子进行了综述。在所综述的6种分子中，有4种的机制与减轻可能导致内耳细胞死亡的氧化应激途径有关。剩下的一种治疗方法试图操纵细胞死亡级联反应，最后一种治疗方法是一种新型的细胞替代疗法，即引入一种促进毛细胞再生的转录因子。
在美国最近注册的临床试验中，一个共同的主题似乎是针对细胞死亡途径以及氧化应激源对耳蜗感觉神经上皮的影响。此外，一种通过病毒递送的细胞替代疗法如果证明安全有效，将是同类疗法中的首例。将这些从实验室到临床的治疗方法推向市场仍面临重大挑战。在人类生物学背景下，非人类动物模型的结果能否转化为有效的治疗方法，这一点从来都不能确定。此外，随着与听力损失相关的其他过程被描述出来，比如免疫反应和突触联系的丧失，可供靶向的额外途径也出现了。
