Early phase trials of novel hearing therapeutics: Avenues and opportunities

Schilder, Anne G. M.; Su, Matthew P.; Mandavia, Rishi; Anderson, Caroline Rachael; Landry, Evie; Ferdous, Tanjinah; Blackshaw, Helen

doi:10.1016/j.heares.2019.07.003

Cited by 18 publications

(14 citation statements)

References 164 publications

(169 reference statements)

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“…A number of pharmacologic interventions to help protect the ear from over-exposure to loud noise appear to be on the horizon, but nothing is FDA-approved yet [248,249]. Hearing aids are helpful but do not restore natural hearing ability, and there is currently no cure for tinnitus or hyperacusis [250], nor for bringing back lost cochlear hair cells and nerve fibers [251][252][253]. NIHL can precipitate depression, social withdrawal, and cognitive decline [254][255][256][257][258][259][260], and mild, moderate, and severe hearing loss increases the risk of dementia by 2-, 3-and 5-fold, respectively [261][262][263].…”

Section: Preventing Noise-induced Hearing Lossmentioning

confidence: 99%

Loud Music and Leisure Noise Is a Common Cause of Chronic Hearing Loss, Tinnitus and Hyperacusis

Pienkowski

2021

IJERPH

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High sound levels capable of permanently damaging the ear are experienced not only in factories and war zones but in concert halls, nightclubs, sports stadiums, and many other leisure environments. This review summarizes evidence that loud music and other forms of “leisure noise” are common causes of noise-induced hearing loss, tinnitus, and hyperacusis, even if audiometric thresholds initially remain within clinically normal limits. Given the huge global burden of preventable noise-induced hearing loss, noise limits should be adopted in a much broader range of settings, and education to promote hearing conservation should be a higher public health priority.

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Section: Preventing Noise-induced Hearing Lossmentioning

confidence: 99%

Loud Music and Leisure Noise Is a Common Cause of Chronic Hearing Loss, Tinnitus and Hyperacusis

Pienkowski

2021

IJERPH

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“…In order to prevent SGC degeneration, many studies have investigated the effect of exogenous administration of neurotrophins, in particular the naturally occurring neurotrophin brain-derived neurotrophic factor (BDNF), which significantly enhances SGC survival in deafened guinea pigs (e.g., [1,[12][13][14][15][16][17][18][19][20]), cats [21,22] and rats [23]. These animal studies pave the way for possible human applications to benefit CI users [24,25], or as a potential treatment to counteract synaptopathy [26,27]. Importantly, treatment of exogenous BDNF does not only have a positive effect on structural survival of the auditory nerve; its responsiveness to electric current pulses, as provided by a CI, is also significantly improved [14,19,21,28].…”

Section: Introductionmentioning

confidence: 99%

BDNF Outperforms TrkB Agonist 7,8,3′-THF in Preserving the Auditory Nerve in Deafened Guinea Pigs

et al. 2020

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In deaf subjects using a cochlear implant (CI) for hearing restoration, the auditory nerve is subject to degeneration, which may negatively impact CI effectiveness. This nerve degeneration can be reduced by neurotrophic treatment. Here, we compare the preservative effects of the naturally occurring tyrosine receptor kinase B (TrkB) agonist brain-derived neurotrophic factor (BDNF) and the small-molecule TrkB agonist 7,8,3′-trihydroxyflavone (THF) on the auditory nerve in deafened guinea pigs. THF may be more effective than BDNF throughout the cochlea because of better pharmacokinetic properties. The neurotrophic compounds were delivered by placement of a gelatin sponge on the perforated round window membrane. To complement the histology of spiral ganglion cells (SGCs), electrically evoked compound action potential (eCAP) recordings were performed four weeks after treatment initiation. We analyzed the eCAP inter-phase gap (IPG) effect and measures derived from pulse-train evoked eCAPs, both indicative of SGC healthiness. BDNF but not THF yielded a significantly higher survival of SGCs in the basal cochlear turn than untreated controls. Regarding IPG effect and pulse-train responses, the BDNF-treated animals exhibited more normal responses than both untreated and THF-treated animals. We have thus confirmed the protective effect of BDNF, but we have not confirmed previously reported protective effects of THF with our clinically applicable delivery method.

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“…Hearing restoration strategies currently under preclinical and early clinical investigation include gene therapy approaches and different modalities to induce tissue repair (reviewed in References 48‐51). The first, focus on gene correction, through gene or base editing, 52‐54 or gene replacement, 55‐58 to modify or bypass genetic defects.…”

Section: Introductionmentioning

confidence: 99%

Directed differentiation and direct reprogramming: Applying stem cell technologies to hearing research

Roccio

2020

Stem Cells

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Hearing loss is the most widely spread sensory disorder in our society. In the majority of cases, it is caused by the loss or malfunctioning of cells in the cochlea: the mechanosensory hair cells, which act as primary sound receptors, and the connecting auditory neurons of the spiral ganglion, which relay the signal to upper brain centers.In contrast to other vertebrates, where damage to the hearing organ can be repaired through the activity of resident cells, acting as tissue progenitors, in mammals, sensory cell damage or loss is irreversible. The understanding of gene and cellular functions, through analysis of different animal models, has helped to identify causes of disease and possible targets for hearing restoration. Translation of these findings to novel therapeutics is, however, hindered by the lack of cellular assays, based on human sensory cells, to evaluate the conservation of molecular pathways across species and the efficacy of novel therapeutic strategies. In the last decade, stem cell technologies enabled to generate human sensory cell types in vitro, providing novel tools to study human inner ear biology, model disease, and validate therapeutics. This review focuses specifically on two technologies: directed differentiation of pluripotent stem cells and direct reprogramming of somatic cell types to sensory hair cells and neurons. Recent development in the field are discussed as well as how these tools could be implemented to become routinely adopted experimental models for hearing research.

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Early phase trials of novel hearing therapeutics: Avenues and opportunities

Cited by 18 publications

References 164 publications

Loud Music and Leisure Noise Is a Common Cause of Chronic Hearing Loss, Tinnitus and Hyperacusis

Loud Music and Leisure Noise Is a Common Cause of Chronic Hearing Loss, Tinnitus and Hyperacusis

BDNF Outperforms TrkB Agonist 7,8,3′-THF in Preserving the Auditory Nerve in Deafened Guinea Pigs

Directed differentiation and direct reprogramming: Applying stem cell technologies to hearing research

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