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

描述(申请人提供)：先天性感音神经性听力损失(SNHL)是美国最常见的神经出生缺陷，先天性CMV是先天性SNHL最常见的原因之一，因此对CMV相关听力损失的安全和有效治疗有着明确的临床需求。幸运的是，现在出现的数据表明，在新生儿期使用更昔洛韦等抗病毒药物可以稳定甚至改善患有先天性巨细胞病毒症状的婴儿的听力。然而，抗病毒疗法广泛使用的一个主要障碍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，使常规使用更昔洛韦、伐更昔洛韦和西多福韦等药物的决定变得困难；特别是在SNHL是疾病的唯一表现的“无症状”先天性CMV感染的情况下。这种临床困境是这项通过鼓室途径将抗病毒药物输送到内耳的临床前动物试验的推动力。根据大量的耳科药物(如皮质类固醇或氨基糖苷类药物)鼓室内注射治疗耳蜗病和内耳的经验，研究人员建议鼓室内注射抗病毒药物(更昔洛韦和西多福韦)可以有效地治疗巨细胞病毒相关性听力损失，同时避免这些抗病毒药物的众多和重大的潜在副作用。他们将使用他们成熟的巨细胞病毒感染和听力损失的豚鼠模型来验证这一假设。巨细胞病毒相关性听力损失首先是通过直接将豚鼠巨细胞病毒(GPCMV)或新产生的嵌合体GPCMV接种到豚鼠幼鼠的耳蜗处而诱导的。然后，实验性抗病毒治疗组将接受鼓室内剂量的药物治疗，并通过进行听性脑干反应(ABR)测试和耳蜗组织病理学检查来监测治疗效果。通过执行这项拟议的研究计划，研究人员将产生新的数据，这些数据将作为早期临床试验的基础，在中耳间隙使用抗病毒药物，以治疗与CMV相关的内耳疾病。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毒性的降低。鉴于婴儿先天性巨细胞病毒感染和SNHL的巨大潜在患者群体，迫切需要进行这些研究并开发安全有效的新疗法。

DESCRIPTION (provided by applicant): With congenital sensorineural hearing loss (SNHL) being the most common neurological birth defect in the U.S. and congenital CMV being 1 of the most common causes of congenital SNHL, 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 SNHL 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, the investigators 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. They will test this hypothesis using their 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, the investigators 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.