Hearing loss due to aging, constant exposure to noise, use of certain cancer therapy drugs, and intake of antibiotics are irreversible. Scientists have for long been unable to reprogram existing cells to develop into the outer and inner ear sensory cells, which are essential for hearing, once they die.
However, scientists at Northwestern University in the United States have now discovered a single master gene that can program ear hair cells into either outer or inner ones, overcoming a major hurdle that had prevented the development of these cells to restore hearing.
The discovery of a clear cell switch that can direct a specific cell to develop into one cell type or the other, provides a previously unavailable tool to make an inner or outer hair cell. Currently, scientists can produce an artificial hair cell, but it does not differentiate into an inner or outer cell, which provide different essential functions to produce hearing. The discovery is a major step in developing these specific cells.
The death of outer hair cells made by the cochlea are most often the cause of deafness and hearing loss. The cells develop in the embryo and do not reproduce. The outer hair cells expand and contract in response to the pressure of sound waves and amplify sound for the inner hair cells. The inner cells transmit those vibrations to the neurons to create the sounds we hear.
The master gene switch that programs the differentiation in the ear hair cells identified by the scientists is labeled TBX2. When the gene is expressed, the cell becomes an inner hair cell. When the gene is blocked, the cell becomes an outer hair cell. The ability to produce one of these cells requires a gene cocktail that includes ATOH1 and GF1 genes, which are needed to make a cochlear hair cell from a non-hair cell. Then the TBX2 would be turned on or off to produce the needed inner or outer cell.
The goal of the researchers was to reprogram supporting cells, which are latticed among the hair cells and provide them with structural support needed to grow into outer or inner hair cells. The success of the study now enables us to specifically make inner or outer hair cells, and to identify why the outer hair cells are more prone to dying and cause deafness, said the scientists. Nevertheless, they cautioned that their research is still in the experimental stage and more studies were needed to take it to the next steps that lead to a clinical solution.
In a related study on restoring hearing, an international team of researchers at University of Rochester in the US, the University of Copenhagen in Denmark, and the Karolinska Institute in Stockholm, Sweden, have developed a new method to deliver drugs into the inner ear that could potentially restore hearing in deaf people. The number of people worldwide predicted to have mild to complete hearing loss is expected to grow to around 2.5 billion by mid-century.
The discovery was made possible by harnessing the natural flow of fluids in the brain and employing a little understood backdoor into the cochlea located in the inner ear. When combined, it enabled the delivery of a gene therapy that repairs inner ear hair cells and restore hearing in deaf mice.
The findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step towards using gene therapy to restore hearing in humans. The primary cause of hearing loss or deafness is the death or loss of function of hair cells in the cochlea that are responsible for relaying sounds to the brain. Several factors can cause the loss or death of ear cells, including mutations of critical genes, aging, constant noise exposure, and other factors.
While hair cells do not naturally regenerate in humans and other mammals, previous studies on gene therapy have shown promise and in separate studies have successfully repaired the function of hair cells in neonatal and very young mice.
However, as both mice and humans age, the cochlea, already a delicate structure, becomes enclosed in temporal bone. At this point, any effort to reach the cochlea and deliver a gene therapy via surgery risks damaging this sensitive area and altering hearing.
In the new study, the researchers described a little understood passage into the cochlea called the cochlear aqueduct a thin boney channel no larger than a single strand of hair. The cochlear aqueduct has been shown to play a role in balancing pressure in the ear, but the new study shows that it also acts as a conduit between the cerebrospinal fluid found in the inner ear and the rest of the brain.
Scientists are only beginning to develop a clearer picture of the mechanics of the glymphatic system, the brain’s unique process of removing waste. Because the glymphatic system pumps cerebrospinal fluid deep into brain tissue to wash away toxic proteins, researchers have been eyeing it as a potentially new way to deliver drugs into the brain, a major challenge in developing drugs for neurological disorders.
Researchers have also discovered that the complex movement of fluids driven by the glymphatic system extends to the eyes and the peripheral nervous system, including the ear. Employing a number of imagining and modeling technologies, the scientists were able to develop a detailed portrait of how fluid from other parts of the brain flows through cochlear aqueduct and into the inner ear. The team then injected an adeno- associated virus into the cisterna magna-a large reservoir of cerebrospinal fluid found at the base of the skull.
The adeno-associated virus, which is composed a single-stranded DNA viral sector- found its way into the inner ear via the cochlear aqueduct, delivered a gene therapy that expressed a protein called vesicular glutamate transporter-3, which enabled the hair cells to transmit signals and restore hearing in adult deaf mice.
The new delivery route into the ear has the potential to serve not only the advancement of auditory research but also prove its usefulness when translated to humans with progressive genetic-mediated hearing loss.
