New molecular therapies for the treatment of hearing loss

doi:10.1016/j.pharmthera.2019.05.003

Pharmacology & Therapeutics

Volume 200, August 2019, Pages 190-209

https://doi.org/10.1016/j.pharmthera.2019.05.003 Get rights and content

Abstract

An estimated 466 million people suffer from hearing loss worldwide. Sensorineural hearing loss is characterized by degeneration of key structures of the sensory pathway in the cochlea such as the sensory hair cells, the primary auditory neurons and their synaptic connection to the hair cells – the ribbon synapse. Various strategies to protect or regenerate these sensory cells and structures are the subject of intensive research. Yet despite recent advances in our understandings of the capacity of the cochlea for repair and regeneration there are currently no pharmacological or biological interventions for hearing loss. Current research focusses on localized cochlear drug, gene and cell-based therapies. One of the more promising drug-based therapies is based on neurotrophic factors for the repair of the ribbon synapse after noise exposure, as well as preventing loss of primary auditory neurons and regrowth of the auditory neuron fibers after severe hearing loss. Drug therapy delivery technologies are being employed to address the specific needs of neurotrophin and other therapies for hearing loss that include the need for high doses, long-term delivery, localised or cell-specific targeting and techniques for their safe and efficacious delivery to the cochlea. Novel biomaterials are enabling high payloads of drugs to be administered to the cochlea with subsequent slow-release properties that are proving to be beneficial for treating hearing loss. In parallel, new gene therapy technologies are addressing the need for cell specificity and high efficacy for the treatment of both genetic and acquired hearing loss with promising reports of hearing recovery. Some biomaterials and cell therapies are being used in conjunction with the cochlear implant ensuring therapeutic benefit to the primary neurons during electrical stimulation. This review will introduce the auditory system, hearing loss and the potential for repair and regeneration in the cochlea. Drug delivery to the cochlea will then be reviewed, with a focus on new biomaterials, gene therapy technologies, cell therapy and the use of the cochlear implant as a vehicle for drug delivery. With the current pre-clinical research effort into therapies for hearing loss, including clinical trials for gene therapy, the future for the treatment for hearing loss is looking bright.

Introduction

Over 5% of the world's population is living with a disabling hearing loss impacting on the individual's ability to communicate with others (WHO, 2018). Despite being a very important part of our lives, hearing is often taken for granted until it begins to deteriorate. The severity of the pathology ranges from loss of the synapse between the hair cells that convert sound input into electrical signals and the spiral ganglion neurons (SGNs) that transmit the electrical signals to the brain, to more severe cases with loss of hair cells and loss of SGNs. There are currently very few treatment options for people with hearing loss. Hearing aids may be used to amplify sounds for people with a mild or moderate hearing loss whereas cochlear implants are suitable for people with more significant hearing loss. While hearing aids and cochlear implants partially reverse the symptoms of hearing loss they do not restore the underlying pathology: cellular degeneration in the cochlea and loss of connection between the cochlea and the central auditory processing areas of the brain. At the pre-clinical level there is mounting evidence of therapeutic protection and/or regeneration of hair cells, SGNs and other affected cell types with numerous examples of hearing protection and hearing recovery. Therapeutic strategies focus on overcoming some of the obstacles of providing safe and efficacious localised drug delivery to the cochlea. This review will provide an overview of the auditory system, hearing loss, capacity for repair and regeneration and the current status of targeted therapies for drug delivery to the cochlea.

Section snippets

Normal cochlear anatomy and function

The peripheral auditory system consists of the external, middle and inner ear - or cochlea. The external auditory canal provides efficient transmission of the acoustic stimulus to the tympanic membrane or ear drum. The middle ear cavity, bound by the tympanic membrane laterally and the cochlea medially, efficiently couples sound energy from the air-filled external auditory canal to the fluid filled cochlea via the ossicular chain consisting of the malleus, incus and stapes (Peake & Rosowski,

Impact on people

Over 432 million adults and 34 million children have a disabling hearing loss, making it a major health and economic burden on society (WHO, 2018). Hearing impairment can result in significant communication disorders including poor development of spoken and written language in children, leading to significant educational, social and vocational ramifications that can adversely affect quality of life. In adults, hearing loss affects employment, income and social interaction and self-esteem (

Delivery of drugs to the inner ear

Drug based therapies targeting inner ear disease have been used clinically for over 60 years, initially using systemic administration to deliver aminoglycosides for the treatment of severe bilateral Meniere's disease, and more recently the application of steroids for sudden SNHL. Although still in clinical practise, these therapies exhibit significant limitations including highly variable pharmacokinetics due to the blood-cochlear barrier and clinical variability (e.g. patient age; renal

Novel cochlear therapy technologies

The key features of a clinically relevant drug delivery strategy are that the system must be capable of delivering a therapeutic dose of the drug safely to the inner ear over durations that are required for a clinically meaningful outcome. The active agent is typically delivered to the round window membrane or to the intracochlear environment depending upon the clinical indication that is being targeted. While there are sophisticated microfluidic based drug delivery pumps under development with

Conclusions

Hearing loss is a significant problem world-wide. The sensory hair cells and SGNs of the cochlea are often affected and do not spontaneously regenerate in humans. A number of factors have been identified that can preserve, repair or regenerate these cell types with a growing number of studies showing recovery of hearing in animal models of acquired and genetic forms of hearing loss. The anatomy of the cochlea presents some unique challenges for the development of a therapy for hearing loss. The

Conflict of interest statement

The authors A.K.W, Y.M and R.K.S are named inventors on a patent describing drug delivery technique that is owned by the Bionics Institute. There is no financial conflict of interest by these or any author.

Acknowledgments

This work was supported by the following funding agencies for which we are most grateful: US Department of Defence Translation Research Award (RH170019), the National Institute on Deafness and other Communication Disorders (R01DC015031), Action on Hearing Loss (G30, G39, G89), the Garnett Passe and Rodney Williams Memorial Foundation, Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (project number CE140100036), the Robert Bulley Foundation and the

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New molecular therapies for the treatment of hearing loss

Abstract

Introduction

Section snippets

Normal cochlear anatomy and function

Impact on people

Delivery of drugs to the inner ear

Novel cochlear therapy technologies

Conclusions

Conflict of interest statement

Acknowledgments

Neuron

Hearing Research

American Journal of Otolaryngology

Hearing Research

Neuroscience Research

Experimental Neurology

Neurobiology of Disease

Hearing Research

Journal of Chronic Diseases

Biomaterials

Hearing Research

Hearing Research

Molecular Therapy

Current Biology

Molecular Therapy — Methods & Clinical Development

Experimental Cell Research

Alzheimer's & Dementia

Behavioural Brain Research

Molecular Therapy

Hearing Research

Molecular Therapy

Hearing Research

The Lancet

Otolaryngology: Head and Neck Surgery

Molecular Therapy — Nucleic Acids

Lancet

Hearing Research

Hearing Research

Molecular Therapy

Molecular Therapy — Methods & Clinical Development

Hearing Research

Hearing Research

Molecular Therapy

Hearing Research

Hearing Research

Maturitas

American Heart Journal

Hearing Research

Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis

The New England Journal of Medicine

Monitoring of cochlear function during cochlear implantation

Laryngoscope

Enhanced survival of spiral ganglion cells after cessation of treatment with brain-derived neurotrophic factor in deafened guinea pigs

Journal of the Association for Research in Otolaryngology

Prosurvival and proapoptotic intracellular signaling in rat spiral ganglion neurons in vivo after the loss of hair cells

The Journal of Comparative Neurology

A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice

EMBO Molecular Medicine

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The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology

Tmc gene therapy restores auditory function in deaf mice

Science Translational Medicine

Neurotrophin gene therapy for sustained neural preservation after deafness

PLoS One

Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs

PLoS One

Regenerated hair cells can originate from supporting cell progeny: evidence from phototoxicity and laser ablation experiments in the lateral line system

The Journal of Neuroscience

Regenerating cochlear hair cells: quo vadis stem cell

Cell and Tissue Research

Enhanced bioavailability of nerve growth factor with phytantriol lipid-based crystalline nanoparticles in cochlea

International Journal of Nanomedicine