Cochlear protein biomarkers as potential sites for targeted inner ear drug delivery

Abstract

The delivery of therapies to the cochlea is notoriously challenging. It is an organ protected by a number of barriers that need to be overcome in the drug delivery process. Additionally, there are multiple sites of possible damage within the cochlea. Despite the many potential sites of damage, acquired otologic insults preferentially damage a single location. While progress has been made in techniques for inner ear drug delivery, the current techniques remain non-specific and our ability to deliver therapies in a cellspecific manner are limited. Fortunately, there are proteins specific to various cell-types within the cochlea (e.g., hair cells, spiral ganglion cells, stria vascularis) that function as biomarkers of site-specific damage. These protein biomarkers have potential to serve as targets for cell-specific inner ear drug delivery. In this manuscript, we review the concept of biomarkers and targetedinner ear drug delivery and the well-characterized protein biomarkers within each of the locations of interest within the cochlea. Our review will focus on targeted drug delivery in the setting of acquired otologic insults (e.g., ototoxicity, noise-induce hearing loss). The goal is not to discuss therapies to treat acquired otologic insults, rather, to establish potential concepts of how to deliver therapies in a targeted, cell-specific manner. Based on our review, it is clear that future of inner ear drug delivery is a discipline filled with potential that will require collaborative efforts among clinicians and scientists to optimize treatment of otologic insults.

Bioinformatic Analysis of the Perilymph Proteome to Generate a Human Protein Atlas

“…Another potent protector for neurons and glial cells could be thymidine phosphorylase (TYMP) since it has been shown to be increased after ischemic injury ( Naples et al, 2020 ). Several other positive effects of TYMP have been reported such as proangiogenic, anti-apoptotic and pro-thrombotic ( Li and Yue, 2018 ).…”

“…Based on the proteome profile of the inner ear as identified by perilymph mass spectrometry analysis and the use of an existing platform (i.e., Pharos), we identified several proteins as molecular targets for already existing drugs ( Table 1 ). The quest for such targets has been emphasised in a recent review collecting experimental data on available protein targets for a focused therapeutic delivery to selected cell types within the inner ear ( Naples et al, 2020 ). This is clinically important because the cochlea is protected from external influences by the hard bony otic capsule, round and oval window membrane as well as the blood labyrinth barrier ( Naples et al, 2020 ).…”

Isolation of sensory hair cell specific exosomes in human perilymph

“…Using immunomagnetic capture-release nano pom-poms, we for the first time demonstrate the presence of exosomes in human perilymph (Figure 2). The presence of the sensory hair cell specific protein myosin VII on the exosomes suggests that at least a subset of exosomes are produced by either auditory or vestibular hair cells (Naples, Miller, Ramsey, delivery, & translational, 2019). Diagnosis of inner ear disease on a molecular or cellular level presents unique challenges due our inability to date to biopsy the inner ear and the complex tissues and multiple pathophysiologic processes involved in hearing loss.…”

“…A diverse population of inner ear cell specific that could potentially be used to select exosomes specific to the inner ear from the serum population followed by either proteomic or PCR analysis of their cargo. The ability to capture exosomes from the serum based on inner ear specific markers could also open the possibility to diagnose inner ear disease on a cellular level since many of the inner ear specific proteins are expressed by particular cell types (Naples et al, 2019). Further studies will be needed in patients with acute and chronic hearing loss to further translate these findings.…”

In‐depth proteome of perilymph in guinea pig model

“…guinea pig, perilymph, proteome Sensorineural hearing loss (SNHL) is caused by disorders of the cochlear sensory epithelium, which is caused by impairment of various structures of the cochlea, including the perilymph-filled scala tympani (ST), scala vestibuli (SV), and the endolymph-filled cochlear duct as well as various type of cells within the cochlea [1]. Because no method currently exists to directly evaluate the biologic changes in the inner ear, diagnosis of SNHL is mostly dependent on hearing threshold tests, leading to limited understanding of SNHL pathophysiology.…”