Hearing Loss Therapies Made Possible by Unlocking Access to the Inner Ear

A recentstudy介绍一种新的手术方法的访问human cochlea, part of the inner ear that plays a key role in our hearing, for the first time. This discovery, developed by an international team of surgeons and researchers, could help pave the way for the development of new cell, gene and drug therapies for hearing loss.

188金宝搏备用spoke toDr.Simon Chandler, CEO of Rinri Therapeutics, which funded the study, to find out more about this new technique.

Sarah Whelan (SW): Hearing loss is incredibly common, yet there is currently no biological treatment available. What are some of the challenges impeding the development of viable treatments for hearing loss?

Simon Chandler(SC):Hearing loss caused by damage to the sensory cells of the inner ear (sensorineural hearing loss) is expected to affect over 700 million people globally by 2050, and yet, currently, the only treatment solutions that exist are palliative medical devices, external prostheses (such as cochlear implants) and hearing aids, which have functional limitations.

The search for a curative treatment for sensorineural hearing loss has been a long and challenging one. There are a number of approaches you could take to repair the inner ear, but the problem is essentially a cellular one – why don’t we just replace the cells? Effectively, to try and restore hearing, we are proposing to transplant cells into the cochlea of patients to replace those that are dead or damaged. If you replace the cells that are dead or damaged, and these can reconnect, you have the potential to restore function in these patients.

SW: Could you tell us why the inner ear has previously been so difficult to access for therapeutic interventions?

SC:The part of the inner ear responsible for hearing is known as the cochlea. It lies at the base of the skull, deeply encased in one of the hardest and densest bones in the human body, the petrous part of the temporal bone. Petrous in Latin means “stone-like, hard”, and the skull base is indeed fit to protect the fragile structures enclosed within it. While this is beneficial for the protection of our hearing structures, its location means that they are intractable to conventional routes of delivery and standard therapeutic interventions.

Aside from the cochlea’s petrous protection, structures within the cochlea – such as the basilar and Reissner’s membranes – are microscopic and are well beyond the resolution of current clinical imaging techniques. While microcomputed tomography (a 3D imaging technique utilizing X-rays to see inside an object) provides sufficient spatial resolution, contrast agents are necessary to differentiate soft tissues. Conventional histological techniques disrupt tissue morphology, so until recently, delineating these minute structures has been very difficult to do, hampering the development of a safe path of access.

SW: The paper describes using synchrotron radiation phase-contrast imaging (SR-PCI) to image the inner ear and identify a route of entry for therapy. Could you briefly explain how SR-PCI works, and some of its advantages over previous technologies?

SC:Conventional methods used to design surgical routes to the cochlea, even those using operating microscopes, have been denounced for their intrinsic destructive nature.

SR-PCI is an imaging technique that allows the user to visualize soft biological tissue without contrast agents, meaning it can show the entire structure and surface boundaries of a specimen in a 3D format. By using SR-PCI instead of other computed tomographies, we wanted to see an accurate, detailed image of the cytoarchitecture of the inner ear. This technology has transformed our ability to display and evaluate the biological tissue of the inner ear.

Our application of SR-PCI to the auditory system coincides with an escalation of interest in regenerative inner ear therapies, which hold considerable promise for addressing the growing health burden of hearing loss.

SW: Could you explain how this proposed route of access to the inner ear was developed and validated from these images?

SC:The images produced using SR-PCI allowed us to see the bony wall of the cochlea, which was made semi-transparent to permit visualization of the internal substructures of the cochlea such as the basilar membrane, Rosenthal’s canal and the auditory nerve. Rosenthal’s canal is particularly important, as it houses the bodies of the neurons that form the nerve. This imaging also allows us to visualize the cochlear blood vessels and to track the pathways of the nerves through to the bony core (modiolus) of the cochlea.

At the base of the cochlea lies the round window membrane, which fortunately is easily identifiable during routine ear surgery. This membrane can be readily penetrated or reflected to access Rosenthal’s canal. We could use the 3D SR-PCI models to define the membrane’s relationship with Rosenthal’s canal and conduct a series of surgical simulations. This created a heatmap to show which surgical application had the highest probability of leading us directly to Rosenthal’s canal. By effectively splitting the round window membrane into a 4x4 grid, we found that setting the point of penetration within the top 2 middle squares of the grid would reach the target in 80% of cases without comprising the cochlea’s blood supply. To facilitate clinical translation, the trajectory of the surgical trephine (probe) wasplannedto be compatible with those used in routine ear surgery.

To confirm access validity, a series of micro-dissections were carried out on six (human) temporal bones to see if Rosenthal’s canal could be targeted using a surgical approach through the mastoid bone (part of the temporal bone behind the ear) using standard instrumentation. Before dissecting, the expected site of Rosenthal’s canal on the specimens was marked using a radio-opaque metallic marker before being scanned by micro-computed tomography. In five of the six temporal bones, the marker was either within Rosenthal’s canal or adjacent to it. The results followed the pattern predicted by the modeling data with no observed damage to anatomical structures of the inner ear.

SW: How do you see these findings being used in the future? For example, in trials of cell and gene therapies for hearing loss?

SC:Rinri Therapeutics is developing regenerative cell therapies for hearing loss, initially targeting auditory nerve-related hearing loss with human pluripotent stem cell-derived otic neural progenitors that can repair auditory nerves. While this has been demonstrated in a mammalian model of nerve-related hearing loss, its translation into humans has been hindered due to limited anatomical knowledge of the cytoarchitecture of the inner ear and the lack of safe access to Rosenthal’s canal.

We hope that this research will facilitate the precise delivery of our novel therapeutic agent to the cochlea. If all goes to plan, Rinri expects to commence clinical trials for its cell therapy, Rincell-1, in 2024.

Dr. Simon Chandler was speaking to Sarah Whelan, Science Writer for Technology Networks.