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.
|Ward, Jonette A; Sidell, Douglas R; Nassar, Michel et al. (2014) Safety of cidofovir by intratympanic delivery technique. Antivir Ther 19:97-105|
|Park, Albert H; Mann, David; Error, Marc E et al. (2013) Comparative analysis of detection methods for congenital cytomegalovirus infection in a Guinea pig model. JAMA Otolaryngol Head Neck Surg 139:82-6|
|Choo, Daniel; Meinzen-Derr, Jareen (2010) Universal newborn hearing screening in 2010. Curr Opin Otolaryngol Head Neck Surg 18:399-404|
|Park, Albert H; Gifford, Thomas; Schleiss, Mark R et al. (2010) Development of cytomegalovirus-mediated sensorineural hearing loss in a Guinea pig model. Arch Otolaryngol Head Neck Surg 136:48-53|
|McGregor, Alistair; Choi, K Yeon; Cui, Xiaohong et al. (2008) Expression of the human cytomegalovirus UL97 gene in a chimeric guinea pig cytomegalovirus (GPCMV) results in viable virus with increased susceptibility to ganciclovir and maribavir. Antiviral Res 78:250-9|