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

先天性感音神经性听力损失(SNHL)是儿童最常见的神经出生缺陷 美和先天性巨细胞病毒是先天性SNHI最常见的原因之一，有明显的临床意义 对巨细胞病毒相关性听力损失安全有效治疗的需求。幸运的是，数据现在正在浮现 这表明，更昔洛韦等抗病毒药物在新生儿期使用时，可以稳定或 甚至改善有症状的先天性巨细胞病毒婴儿的听力。然而，一个主要的威慑因素是 抗病毒治疗的广泛使用是与全身给药相关的副作用。 造血和肾脏毒性，可能的致癌和生精作用使决定 常规使用更昔洛韦、伐更昔洛韦和西多福韦等药物有困难；特别是在 “无症状”的先天性巨细胞病毒感染，SNHI是疾病的唯一表现。这个诊所 两难境地是这项通过内耳输送抗病毒药物的临床前动物试验的推动力 鼓室内进路。借鉴了鼓室内给药的丰富耳科经验 治疗耳蜗病和内耳的药物(如皮质类固醇或氨基糖苷类药物)，我们建议 鼓室内注射抗病毒药物(更昔洛韦和西多福韦)可有效治疗CMV- 相关的听力损失，同时避免这些抗病毒药物的众多和重大的潜在副作用 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验证这一假设。 损失。巨细胞病毒相关的听力损失首先是通过直接接种到豚鼠幼鼠的耳蜗处造成的 豚鼠巨细胞病毒(GPCMV)或新产生的嵌合GPCMV。实验性抗病毒治疗组 然后接受鼓室内剂量的药物和通过进行听觉监测的治疗效果 脑干反应(ABR)检测和耳蜗组织病理学检查。通过执行以下命令 提出的研究计划，我们将产生新的数据，作为早期临床试验的基础 向中耳间隙注射抗病毒药物，以治疗巨细胞病毒相关性内耳疾病。这个 鼓室内注射抗病毒药物的潜在好处包括疗效上的优势以及减少 毒物。鉴于婴儿先天性巨细胞病毒感染的潜在患者数量巨大， SNHL，迫切需要进行这些研究并开发安全有效的新疗法。

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.