Future Medical Management of Hearing Loss

Introduction

The lecture discusses emerging treatments for hearing loss and the audiologist's role in patient advocacy and education.
Some treatments are in phase two clinical trials and expected to become available during the students' clinical audiology careers.
Patients are already asking about alternatives to cochlear implants, such as stem cell therapy. So clinicians must be well-informed.
The lecturer has been involved in the development of these therapies for 25 years and will share the background, roadblocks, and current status of these treatments.

Learning Objectives

Evaluate and understand the current state and limits of technology and interventions for hearing loss.
Justify the role of audiologists in patient advocacy and education.
Name two regenerative treatments for sensorineural hearing loss.
Understand the targets for these therapies (hair cells, neurons, synapses).
Describe how different treatments address underlying pathologies of sensorineural hearing loss.
Understand the efficacy of these treatments and how to manage and measure it over time.
Communicate how the therapies work to clients and direct them to further information.

Prevalence and Prevention of Hearing Loss

Hearing loss is the third most common chronic physical condition in the US, ahead of diabetes and cancer in adults.
Predicted to increase, affecting about 10% of the global population.
Much of hearing loss is preventable through education and awareness of its irreversible nature.
Unsafe listening practices, especially among 18-25 year olds, are a major concern.
The best way to avoid hearing loss is prevention, particularly noise-induced hearing loss.

Current Treatments vs. Emerging Therapies

No current drug or treatment can reverse the cellular damage of sensorineural hearing loss.
Current treatments (cochlear implants, hearing aids) address the problem but not the underlying cause.
Emerging therapies aim to restore function to damaged cells.
Hearing loss impacts educational and employment opportunities, increases social isolation, depression, and dementia risk, and raises the risk of falls due to vestibular involvement.
Two key sensory structures in the temporal bone (inner ear) require protection.

Types of Hearing Loss

Conductive hearing loss is typically treated with hearing aids or surgery.
Sensorineural hearing loss involves damage to sensory cells and can potentially be regenerated or repaired.
Mixed hearing loss can result from genetics, infections, or head trauma.
Current treatments for sensorineural hearing loss include devices, surgery, and training programs, but these only treat symptoms, not the cause.
Timely monitoring, detection, and treatment of hearing loss across the lifespan are essential.

Cochlear Anatomy Review

The lecture emphasizes the importance of understanding cochlear anatomy to comprehend the challenges and goals of cell and gene therapies.
Fluid-filled compartments:
- Scala vestibuli: perilymph
- Scala tympani: perilymph
- Scala media (cochlear duct): endolymph
Reissner's membrane separates the scala vestibuli and scala media.
Basilar membrane supports the organ of Corti.
Stria vascularis is located on the outer wall of the scala media.
Tectorial membrane overlays the hair cells in the organ of Corti.
Neurons:
- Housed in Rosenthal's canal.
- Cell bodies send axons that form the eighth nerve.
- Dendrites extend to innovate hair cells.
Cochlear implant placement: scala tympani

Challenges in Developing Therapies

The presented histological section depicts a profoundly deaf cochlea with severe damage.
The absence of hair cells and the collapsed organ of Corti indicate a scar, making regeneration difficult.
Experimental models are used to mirror human hearing loss.
Loss of hair cells can lead to secondary degeneration of neurons, which is problematic for cochlear implant efficacy.
Modern therapies target hair cell regeneration or neuron regeneration.
The goal is to target moderate hearing loss first and then iterate therapies towards more severe cases.

Gene and Cell Therapies

Two main types of therapies are discussed: gene therapies and cell therapies (stem cell therapy).
These therapies are currently in phase one and two clinical trials.
Both require precision surgical approaches.
Precision surgery is needed to deliver cells and genes into the fluid-filled spaces of the cochlea without leakage.
20 years of development have led to effective ways to deliver cells and genes into the inner ear.
Examples of gene therapies include neurotrophins (NTs) and optogenetics.

Gene Therapies

Neurotrophins (NTs): Growth molecules that regrow nerves in a targeted direction when reintroduced into a mature cochlea.
Optogenetics: Genetically modifying neurons in the cochlea with an opsin (light-sensitive channel) to create optical stimulators.
Example: 801 gene therapy aims to deliver a transcription factor for hair cell production.
Observed result: Increased number of hair cells but incorrect orientation of stereocilia bundles, affecting functionality.

Surgical Approaches for Gene and Cell Delivery

Various approaches have been tried to deliver cells and genes into the cochlea, including:
- Cochleostomy (similar to cochlear implant surgery)
- Round window membrane injection
- Injection into semicircular canals
These methods result in variable transfection across hair cells, with better transfection in apical regions.
Newer techniques involve perfusion through the cochlea, drilling a tiny hole between the anterior and posterior crus of the stapes.
Perfusion allows for prolonged pumping of viral vectors, yielding effective results.

Gene Transfer Therapy Video

Genes are sections of DNA that instruct cells to make proteins.
Genetic conditions can result from changes in genes that affect protein production or function.
Gene therapy involves adding new DNA or changing existing DNA.
Gene transfer therapy delivers new DNA to cells to improve their function.
Vectors (modified viruses, fat molecules, nanoparticles) are used to deliver genes to cells.
Delivery can be done in vivo (inside the body) or ex vivo (outside the body).

Early Gene Therapy Work

Early work involved injecting viral vectors into the scala media to transfect cells.
Vectors were tagged with green fluorescent protein (GFP) for tracking.
Early experiments showed the importance of targeting gene delivery to early time points, when some residual structure remains.
Neurotrophins were delivered to regenerate peripheral dendrites and preserve nerves for cochlear implant stimulation.

Neurotrophin Gene Therapy

Neurotrophins can be genetically expressed to preserve nerves and promote neuron survival.
Transfected hair cells express neurotrophin and attract peripheral dendrites.
This can lead to reduced thresholds for activation of neurons and lower power use with cochlear implants.

COACH clinical trial

A clinical trial is underway in Sydney testing neurotrophin production inside the cochlea.
This approach involves perfusing the cochlea after opening it for an implant to deliver neurotrophins.
The neurotrophins leads to the peripheral dendrites growing out towards the electrode array, reducing the thresholds required for activation in cochlear implant patients.

Optical Stimulation (Optogenetics)

Electrical stimulation in the cochlea can cause broad activation of neuron populations.
Optical stimulation aims to achieve more discrete activation using tiny electrodes with miniaturized LEDs.
This requires genetically modifying neurons with an opsin to make them light-sensitive.
Optical stimulation allows for modulation of neuron activity by inhibiting or activating specific populations.
This may lead to a more normal sense of sound and better music appreciation with cochlear implants.

Challenges with Gene Transfection

Apical and middle regions of the cochlea are easier to transfect than basal regions.
Research is ongoing to improve gene delivery and expression in specific cochlear regions.
The perfusion and fenestration technique have helped overcome these challenges.

Stem Cell Therapies: Neural Replacement

Replacing hair cells with stem cells is challenging due to delivery difficulties and the unique environment of the scala media.
Stem cell therapy for neural replacement is more feasible, as neurons can be targeted in Rosenthal's canal or placed directly onto the eighth nerve.
This approach is being explored for auditory neuropathy and to increase neural population for cochlear implant users.
Rinri Therapeutics is in phase one clinical trials for neural replacement, using human stem cells engineered to be biocompatible.

Rinri Therapeutics Video

Rinri is developing cell therapies to regenerate auditory neurons.
This therapy aims to re-establish nerve connections in the cochlea and reverse neural hearing loss.
Rinri's therapy is based on delivering therapeutic progenitor cells to the inner ear, which can become mature auditory neurons and restore nerve connections.
The goal is a permanent and invisible treatment that transforms lives and reduces pressure on healthcare systems.

Stem Cell Therapy Challenges

Key considerations are delivery, survival, and differentiation of cells.
Stem cells must differentiate into auditory neural progenitors.
The gold standard is determining if cells reconnect and make tonotopic synapses.
Electrical stimulation may help neurons reconnect and establish pathways.
Potential for central plasticity to play a role in relearning to map sound.
Adult population might get more benefit since children are often born without working neurones.

Rinrhi and awareness of the cell therapies that are coming out.

Clients are asking clinicians more about these options.
There are very few clinician or patient resources available to get information about these options.

Odorferlin Gene Therapy Trial

Odorferlin is a protein essential for chemical messaging between hair cells and neurons.
It docks the ribbon synapse to the base of the cell for quick vesicle release.
Patients with full hair cell complements may lack this protein.
Structure is there and all we need to do is put in a good copy of this protein so that we can now dock a vesicle to a membrane.

Surgical Procedure

Perfusion technique involves drilling a fenestration in the stapes footplate and perfusing genes into the scala tympani.
Modified viral vectors can be moved along the cochlea by the use of miniture pumps.
Vectors perfuse throughout the cochlea and out the round window.

Dual Vector System

If there is a large gene that doesn't fit into a vector they can actually split the gene into two different parts, a C and an N terminal part, and they put them in different vectors, so it's a dual vector and put them both in together.
Both of those vectors actually enter the cell nucleus and then they combine inside the nucleus to make a perfect copy of the gene and therefore the protein.
This helps in the anatomy of having an anatomically system, making a new protein is easy at this point.

Trial Results

16 patients were screened for the clinical trial, but only 5 met the criteria based on gene sequencing.
All five patients received bilateral injections.
Videos show remarkable improvements in hearing among these patients.
Improvements lead to a recovery back to mostly moderate hearing that's useable.
Potential for combining cell and gene therapies depends on early detection.

Key Barriers to Translation

Heterogeneous, varied causes of most hearing loss.
Multiple types of gene therapies in one session may be needed.
New diagnostics may to work out where the cell needs improvement better are needed.
Also early detection is a necessity.