Gene therapy can treat genetic hearing loss in neonatal mice. However, treating adult animals is harder because of the location of the cochlea and the risk of damage to inner ear structures. Now, a new study by an international team of researchers demonstrates a new method to deliver drugs into the inner ear. Using the natural flow of cerebrospinal fluid and the cochlear aqueduct to deliver a gene therapy that repairs inner ear hair cells, the researchers were able to restore hearing in deaf mice.

Their findings are published in Science Translational Medicine in an article titled, “Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice.”

“Inner ear gene therapy has recently effectively restored hearing in neonatal mice, but it is complicated in adulthood by the structural inaccessibility of the cochlea, which is embedded within the temporal bone,” wrote the researchers. “Alternative delivery routes may advance auditory research and also prove useful when translated to humans with progressive genetic-mediated hearing loss. Cerebrospinal fluid flow via the glymphatic system is emerging as a new approach for brain-wide drug delivery in rodents as well as humans. The cerebrospinal fluid and the fluid of the inner ear are connected via a bony channel called the cochlear aqueduct, but previous studies have not explored the possibility of delivering gene therapy via the cerebrospinal fluid to restore hearing in adult deaf mice. Here, we showed that the cochlear aqueduct in mice exhibits lymphatic-like characteristics.”

“These 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,” said Maiken Nedergaard, MD, DMSc, a professor at the Center for Translational Neuromedicine, Univerity of Copenhagen and a senior author of the new study.

While hair cells do not naturally regenerate in humans and other mammals, gene therapies 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 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 passage into the cochlea called the cochlear aqueduct. Using a number of imagining and modeling technologies, the researchers were able to develop a detailed portrait of how fluid from other parts of the brain flows through the cochlear aqueduct and into the inner ear. The researchers then injected an adeno-associated virus into the cisterna magna, a large reservoir of cerebrospinal fluid found at the base of the skull. The virus found its way into the inner ear via the cochlear aqueduct, delivered a gene therapy that expresses a protein called vesicular glutamate transporter-3, which enabled the hair cells to transmit signal and rescue hearing in adult deaf mice.

“This new delivery route into the ear may not only serve the advancement of auditory research, but also prove useful when translated to humans with progressive genetic-mediated hearing loss,” said Nedergaard.

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