A preclinical trial of intratympanic antivirals for CMV-related hearing loss

先天性感音神经性听力损失（SNHL）是最常见的神经性出生缺陷， 美国先天性CMV是先天性SNHI最常见的原因之一， 对CMV相关听力损失的安全有效治疗的需求。幸运的是，数据显示 这表明，抗病毒药物，如更昔洛韦，当在新生儿期给药，可以稳定或 甚至可以改善有症状的先天性CMV婴儿的听力。然而，一个主要的威慑力量， 抗病毒治疗的广泛使用是与全身给药相关的副作用。 造血和肾毒性、可能的致癌和致精子作用决定 常规使用药物，如更昔洛韦，缬更昔洛韦和西多福韦困难;特别是在设置 “无症状”先天性CMV感染，其中SNHI是疾病的唯一表现。本临床 这种两难的局面推动了这项临床前动物试验， 鼓室内途径根据大量的耳科经验， 药物（如皮质类固醇或氨基糖苷类）治疗耳蜗和内耳，我们建议， 抗病毒剂（更昔洛韦和西多福韦）的鼓室内递送可用于有效治疗CMV- 相关的听力损失，同时避免这些抗病毒药物的众多和显着的潜在副作用， 毒品我们将使用我们成熟的巨细胞病毒感染和听力的豚鼠模型来检验这一假设 损失CMV相关的听力损失首先通过直接刺激豚鼠幼仔的耳蜗来诱导， 豚鼠CMV（GPCMV）或新产生的嵌合GPCMV。实验性抗病毒治疗组 然后将接受鼓室内剂量的药物，并通过进行听觉监测治疗的效果。 脑干反应（ABR）测试和耳蜗的组织病理学检查。通过执行该 根据拟议的研究计划，我们将产生新的数据，作为早期临床试验的基础。 向中耳腔施用抗病毒药物以治疗CMV相关的内耳疾病。的 鼓室内递送抗病毒药物的潜在益处包括在功效方面的优势以及降低的 毒性考虑到先天性CMV感染的婴儿的巨大潜在患者群体， SNHL，这是令人信服的追求这些研究和开发新的疗法是安全和有效的。

With congenital sensorineural hearing loss (SNHL) being the most common neurological birth defect in the U.S. and congenital CMV being one of the most common causes of congenital SNHI, there is a clear clinical demand for safe and effective treatments for CMV-related hearing loss. Fortunately, data are now emerging that show that antiviral drugs such as ganciclovir, when administered in the neonatal period, can stabilize or even improve hearing in infants with symptomatic congenital CMV. However, a major deterrent to the widespread use of antiviral therapies are the side effects associated with systemic administration. Hematopoetic and renal toxicities, possible carcinogenic and aspermatogenic effects make the decision to routinely use drugs such as ganciclovir, valganciclovir and cidofovir difficult; particularly in the setting of "asymptomatic" congenital CMV infection where SNHI is the only manifestation of disease. This clinical dilemma serves as the impetus for this preclinical animal trial of delivering antiviral drugs to the inner ear via an intratympanic route. Drawing upon the vast otologic experience with intratympanic administration of drugs (such as corticosteroids or aminoglycosides) to treat the cochlea and inner ear, we propose that the intratympanic delivery of antiviral agents (ganciclovir and cidofovir) can be used to effectively treat CMV- related hearing loss while avoiding the numerous and significant potential side effects of these antiviral drugs. We will test this hypothesis using our well-developed guinea pig model of CMV infection and hearing loss. CMV-related hearing loss is first induced by directly inoculating the cochleas of guinea pig pups with guinea pig CMV (GPCMV) or newly generated chimeric GPCMV. Experimental antiviral treatment groups will then receive intratympanic doses of drug and the effects of therapy monitored by performing auditory brainstem response (ABR) testing and histopathologic examination of the cochleas. By executing this proposed research plan, we will generate novel data that will serve as the foundation for early clinical trials administering antiviral drugs to the middle ear space in order to treat CMV-related inner ear disease. The potential benefits of delivering antivirals intratympanically include advantages in efficacy as well as reduced toxicities. Given the tremendous potential patient population of infants with congenital CMV infection and SNHL, it is compelling to pursue these studies and develop new therapies that are safe and effective.