Animal model studies yield translational solutions for cochlear drug delivery

Frisina, Robert D.; Budzevich, Mikalai M.; Liu, Hanjun; Martinez, Gary V.; Walton, Joseph P.; Borkholder, David A.

doi:10.1016/j.heares.2018.05.002

Cited by 11 publications

(7 citation statements)

References 73 publications

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“…Therefore, aside from using systemic estrogen as a therapy, localized use may be the better choice to apply estrogen and its derivatives to improve hearing impairment. Some strategies for cochlear drug delivery such as nanoparticles, hydrogels, or micropumps can be the focus of future investigations [ 143 , 144 ].…”

Section: The Effect Of Hormone Therapy On Hearingmentioning

confidence: 99%

Sex Differences in the Triad of Acquired Sensorineural Hearing Loss

Lien

Yang

2021

IJMS

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The triad of noise-generated, drug-induced, and age-related hearing loss is the major cause of acquired sensorineural hearing loss (ASNHL) in modern society. Although these three forms of hearing loss display similar underlying mechanisms, detailed studies have revealed the presence of sex differences in the auditory system both in human and animal models of ASNHL. However, the sexual dimorphism of hearing varies among noise-induced hearing loss (NIHL), ototoxicity, and age-related hearing loss (ARHL). Importantly, estrogen may play an essential role in modulating the pathophysiological mechanisms in the cochlea and several reports have shown that the effects of hormone replacement therapy on hearing loss are complex. This review will summarize the clinical features of sex differences in ASNHL, compare the animal investigations of cochlear sexual dimorphism in response to the three insults, and address how estrogen affects the auditory organ at molecular levels.

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Section: The Effect Of Hormone Therapy On Hearingmentioning

confidence: 99%

Sex Differences in the Triad of Acquired Sensorineural Hearing Loss

Lien

Yang

2021

IJMS

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“…Despite advances in our understanding of the pathophysiology of cochlear ageing as well as methods to deliver drugs locally to the cochlea [15], pharmaceutical treatments for presbycusis still do not exist. The lack of pharmaceutical treatments for ARHL is in stark contrast to the increasing number of drugs available to treat other age-related conditions.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss

2022

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Age-related hearing loss (ARHL) or presbycusis is a prevalent condition associated with social isolation, cognitive impairment, and dementia. Age-related changes in the cochlea, the auditory portion of the inner ear, are the primary cause of ARHL. Unfortunately, there are currently no pharmaceutical approaches to treat ARHL. To examine the biological processes underlying age-related changes in the cochlea and identify candidate drugs for rapid repurposing to treat ARHL, we utilized bulk RNA sequencing to obtain transcriptomes from the functional substructures of the cochlea—the sensorineural structures, including the organ of Corti and spiral ganglion neurons (OC/SGN) and the stria vascularis and spiral ligament (SV/SL)—in young (6-week-old) and old (2-year-old) C57BL/6 mice. Transcriptomic analyses revealed both overlapping and unique patterns of gene expression and gene enrichment between substructures and with ageing. Based on these age-related transcriptional changes, we queried the protein products of genes differentially expressed with ageing in DrugBank and identified 27 FDA/EMA-approved drugs that are suitable to be repurposed to treat ARHL. These drugs target the protein products of genes that are differentially expressed with ageing uniquely in either the OC/SGN or SV/SL and that interrelate diverse biological processes. Further transcriptomic analyses revealed that most genes differentially expressed with ageing in both substructures encode protein products that are promising drug target candidates but are, nevertheless, not yet linked to approved drugs. Thus, with this study, we apply a novel approach to characterize the druggable genetic landscape for ARHL and propose a list of drugs to test in pre-clinical studies as potential treatment options for ARHL.

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“…This reflects the increasing number of novel therapeutics in pre-clinical development, and to some extent, the challenges of locally delivering therapeutics in humans. Whilst animal models play a vital role in the development of delivery methods, and the testing of novel inner ear therapeutics (Frisina et al, 2018), their applicability to humans is unclear (Denayer et al, 2014; Le Prell et al, 2016; Frisina et al, 2018). There remain significant challenges in translating from animals to humans due to differences in anatomy (thinner bone overlying cochlea; Mikulec et al, 2009), size (smaller cochlea allows greater diffusion; Salt, 2008), and disease models (ISSNHL difficult to replicate).…”

Section: Discussionmentioning

confidence: 99%

Local Delivery of Therapeutics to the Inner Ear: The State of the Science

Anderson

Xie

et al. 2019

Front. Cell. Neurosci.

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Background: Advances in the understanding of the genetic and molecular etiologies of inner ear disorders have enabled the identification of therapeutic targets and innovative delivery approaches to the inner ear. As this field grows, the need for knowledge about effective delivery of therapeutics to the inner ear has become a priority. This review maps all clinical and pre-clinical research published in English in the field to date, to guide both researchers and clinicians about local drug delivery methods in the context of novel therapeutics.Methods: A systematic search was conducted using customized strategies in Cochrane, pubmed and EMBASE databases from inception to 30/09/2018. Two researchers undertook study selection and data extraction independently.Results: Our search returned 12,200 articles, of which 837 articles met the inclusion criteria. 679 were original research and 158 were reviews. There has been a steady increase in the numbers of publications related to inner ear therapeutics delivery over the last three decades, with a sharp rise over the last 2 years. The intra-tympanic route accounts for over 70% of published articles. Less than one third of published research directly assesses delivery efficacy, with most papers using clinical efficacy as a surrogate marker.Conclusion: Research into local therapeutic delivery to the inner ear has undergone a recent surge, improving our understanding of how novel therapeutics can be delivered. Direct assessment of delivery efficacy is challenging, especially in humans, and progress in this area is key to understanding how to make decisions about delivery of novel hearing therapeutics.

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Animal model studies yield translational solutions for cochlear drug delivery

Cited by 11 publications

References 73 publications

Sex Differences in the Triad of Acquired Sensorineural Hearing Loss

Sex Differences in the Triad of Acquired Sensorineural Hearing Loss

Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss

Local Delivery of Therapeutics to the Inner Ear: The State of the Science

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