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

描述（由申请人提供）：先天性感音神经性听力损失（SNHL）是美国最常见的神经性出生缺陷，先天性巨细胞病毒是先天性SNHL最常见的病因之一，因此对CMV相关听力损失的安全有效治疗有明确的临床需求。幸运的是，现在出现的数据表明，在新生儿期使用抗病毒药物，如更昔洛韦，可以稳定甚至改善有症状的先天性巨细胞病毒婴儿的听力。然而，广泛使用抗病毒治疗的主要障碍是与全身给药相关的副作用。造血和肾脏毒性，可能的致癌和致曲霉作用，使得决定常规使用更昔洛韦、缬更昔洛韦和西多福韦等药物变得困难；特别是在“无症状”先天性巨细胞病毒感染的情况下，SNHL是疾病的唯一表现。这种临床困境推动了这项通过鼓室内途径向内耳输送抗病毒药物的临床前动物试验。根据鼓室内给药（如皮质类固醇或氨基糖苷类）治疗耳蜗和内耳的大量耳科经验，研究人员提出，鼓室内给药抗病毒药物（更昔洛韦和西多福韦）可用于有效治疗巨细胞病毒相关的听力损失，同时避免这些抗病毒药物的大量和显著的潜在副作用。他们将使用他们完善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。首先将豚鼠巨细胞病毒（GPCMV）或新生成的嵌合GPCMV直接接种豚鼠幼鼠耳蜗诱导巨细胞病毒相关性听力损失。试验性抗病毒治疗组随后将接受鼓室内剂量的药物，并通过执行听觉脑干反应（ABR）测试和耳蜗组织病理学检查来监测治疗效果。通过执行这一拟议的研究计划，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，为中耳空间施用抗病毒药物，以治疗巨细胞病毒相关的内耳疾病。非对称给药抗病毒药物的潜在好处包括疗效和降低毒性方面的优势。鉴于先天性巨细胞病毒感染和SNHL婴儿的巨大潜在患者群体，开展这些研究并开发安全有效的新疗法是迫切需要的。

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.