The Translational Hearing Research Summit was organised by Action on Hearing Loss, the University College London (UCL) Ear Institute and the NIHR UCLH Biomedical Research Centre (BRC) Deafness and Hearing Loss theme. This unique event brought together almost 200 delegates, patients, scientists, clinicians, commissioners, investors and industry representatives from all over the world to discuss the opportunities and challenges in the translation of hearing loss and tinnitus research. Translational research builds on basic scientific research to create new treatments; it ‘translates’ basic scientific findings in a laboratory to potential new treatments.

Currently multiple management options for people with hearing loss and tinnitus exist and are used in clinical practice such as hearing aids, different modes of sound therapy and cochlear implants. Great technological progress have been made in making those management options better and more effective. However currently there are no approved treatments for tinnitus and hearing loss. The idea behind the event was that collaboration and dialogue between different stakeholders will lead to development of new treatment options.

The summit started with the talk by Prof Douglas Hartley (University of Nottingham) who pointed to the fact that even the most advanced medical devices such as hearing aids and cochlear implants are only partially restoring hearing. Despite these devices transforming lives of people with hearing problems, they often do not perform in the optimal way in the real life listening situations. Therefore he strongly advocated a need for step-change and exploring new avenues for treatment of hearing loss and tinnitus.

The summit concentrated on ‘biological and pharmacological’ approaches which included innovative drug, gene and cell-based interventions to address hearing loss and tinnitus. As nicely summarised in Prof Jonathan Gale’s talk these therapies can have different aims targeting different mechanisms of hearing loss and tinnitus. Those therapeutic targets include protecting and preventing hearing loss (i.e. protecting and preventing damage to hair cells in the cochlea), regulating abnormal brain activity resulting from hearing loss and tinnitus, and restoring or regenerating damaged hair cells and auditory nerve fibres.

Gene therapy

Gene therapy is an experimental technique that uses genes to treat or prevent disease. In most gene therapy studies, a ‘normal’ gene is inserted into the genome to replace an ‘abnormal’, disease-causing gene. A carrier called a vector must be used to deliver the therapeutic gene to the patient's target cells. It is worth noting that this technology is still in its infancy, but it has been used with some success.

More than 90 percent of hearing loss occurs when either hair cells or auditory nerve cells are destroyed. While those cells can regenerate in some species (fish, amphibians, birds) they do not regenerate in mammals including humans. Gene therapy to regenerate sensory hair cells in the cochlea and auditory neurones has been explored as a treatment for hearing loss.

Richard Colvin (Novartis, USA) presented a study that explored the use of Atoh1 gene to regenerate hair cells in the cochlea. Atoh1 is involved in creation of the hair cells while the baby is developing in the uterus but becomes inactive after birth. The study explored the possibility to express Atoh1 gene in humans in order to convert so called supporting cells in the cochlea into functional hair cells.

Gary Housley (Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, Sydney) presented a study that uses gene therapy to regenerate nerve cells that send the sound signal from cochlea to the brain in cochlear implant users. The goal of the study is to enhance the performance of cochlear implant by ‘closing the gap’ between electrodes of the cochlear implant and nerve cells.

Both of the above projects are currently at the stage of early clinical trials, meaning that first studies in humans are ongoing or about to start. However it can take years for those therapies to be available to patients (if successful). There are several challenges when using gene therapy. One is to make sure that the gene is expressed only when needed and for as long as needed. Another is getting the carrier (vector) with the gene where it needs to work in the ear. In addition further research is needed that will explore how to encourage newly-generated hair cells to send appropriate signals to the brain.

Stem cell therapy

Stem cells are cells that can differentiate into other types of cells and can divide to produce more of the same type of stem cells. In mammals, including humans, there are two broad types of stem cells: embryonic stem cells and adult stem cells (found in various tissues). Bone marrow transplantation is an example of using adult stem cells for therapy.

Prof Marcelo Rivolta (Sheffield University, UK) presented his work using human embryonic stem cells to create a type of ear cell called an ‘otic progenitor’. That cell is the 'predecessor' of both hair cells and auditory nerve cells and was used to repair damage to the auditory nerve in deaf animals, restoring their hearing. While the study is currently exploring the use of stem cells to restore damaged nerve cells there is a possibility to attempt to restore other types of cells in the future. There is also potential to combine stem cell therapy with technology such as cochlear implantation to enhance performance of the implant.

One of the main challenges of stem cell therapy is that cells could travel into another areas beyond the inner ear or divide uncontrollably and form tumours, therefore the research concentrates on the safe delivery of the stem cells to the target area.

Drug therapy

Pharmacological approaches presented at the summit included medications that could prevent or treat hearing loss and/or tinnitus.

Guillaume Duvey (Pragma Therapeutics, France) presented work that aims to develop the drug that acts at glutamate receptors. Glutamate plays an important role in the transmission of signals from the ear to the cochlea but excessive noise (acoustic trauma) can cause excessive release of the glutamate in the cochlea which can cause damage to the nerve cells leading to hearing loss. The drug aims to reduce that excessive release of glutamate. Another approach presented by Dr Roland Schaette involved drugs that regulate the activity of potassium ion channels present on certain nerve cells important for hearing. Animal studies showed a link between those channels in auditory areas with hearing problems, including tinnitus. Both of those approaches are still in early phase development and are yet to be tested in humans.

One of the topics presented was prevention of ototoxicity. Ototoxicity is the property of the medication to be toxic to the ear (cochlea, auditory nerve) which can lead to hearing loss and tinnitus. We know that certain medications such as life-saving cancer or antibiotic treatments can cause hearing loss as a side effect. Penelope Brock (Great Ormond Street Hospital, London) presented results of the study that looked at medication to prevent ototoxicity caused by cisplatin treatment for liver cancer in children and Edwin Rubel (University of Washighton and Oricula Therapeutics Inc, Seattle, USA) talked about a drug to prevent aminoglycoside antibiotics induced hair cell damage. The particular challenge of such approaches is to protect hearing but do not interfere with drug therapy, therefore exploring optimal timing for administration of such drugs is crucial.  

Drug delivery

As mentioned before, targeted (in the right place and at the right amount) drug delivery is crucial for effectiveness of the above therapies. Alan Foster (Otonomy Inc.) presented effective ways of drug delivery to the inner ear (through tympanic membrane which could be applied to delivery of novel small molecules and biologics to alleviate hearing loss and tinnitus as well as therapeutics for protection and regeneration of cochlear hair cells in age-related, noise, chemotherapy or genetic hearing loss. Dr Benjamin Shapiro (Otomagnetics, USA) talked about magnetic delivery of therapy to the cochlea and presented the device that works like ‘magnetic syringe’.

Future clinical trials in hearing loss and tinnitus

A lot of discussions and several talks including expert panel discussion concentrated around challenges and further work needed to increase the number of new trials exploring potential treatments for hearing loss and tinnitus. Two perspectives, represented by researchers and industry partners looked at current state of the field in a very different way.

Researchers stressed the incredible progress over the last years in understanding potential mechanisms involved in hearing loss and generation of tinnitus and large number of potential targets for new therapies. On the other hand industry partners perceive hearing and tinnitus treatments area as high risk and not fully meeting criteria for pharmaceutical companies to take projects on. It is worth noting that the drug discovery process is lengthy and expensive and it is not unusual for it to take well over 10 years. While our knowledge of causes of hearing loss and tinnitus increased greatly over the last years, the exact mechanisms and which of them play role in different people are still not fully understood. The identification of therapeutic targets from the plethora of potential mechanisms is crucial. Another issue is lack of biomarkers (medical signs, objective indications of medical state, which can be measured accurately and reproducibly) which are routinely used at different stages of the treatment development process as well as outcome measures that reflect real world conditions. It is also possible that some treatments will only be effective in certain populations of patients, therefore better diagnostics to identify populations that might benefit the most is crucial.

Despite the above challenges it was encouraging to see different stakeholders and disciplines willing to work together to address the above issues. Prof Anne Schilder (UCL Ear Institute, NIHR UCLH BRC) and Dr Charles Large (Autifony Therapeutics, UK) shared their experiences and lessons learnt from large, multicentre clinical trials they were involved in. Prof Deborah Hall (University of Nottingham, NIHR Nottingham BRC) presented international research programme aiming at identifying a minimum standard for assessing how a tinnitus treatment has worked (Core Outcome Measures in Tinnitus initiative). Future work and research should be multidisciplinary and involving industry partners to address gaps preventing translation of the scientific findings into treatments in order to ensure maximum benefit for patients.