Gene Therapy Helps Deaf Mice Hear

New research published in the journal Science Translational Medicine suggests that gene therapy treatments for inherited types of deafness might one day become a reality. This new report shows that fixing faulty DNA sequence in deaf mice can improve their auditory responses. In separate experiments, the drug-maker Novartis is testing a different form of gene therapy in people who have lost their hearing through damage or disease.

Safety missteps in the late 1990s and early 2000s set gene therapy research back several years. During those darker days, gene therapy scientists re-tooled and re-examined their basic assumptions about gene therapy. Even though gene therapy experiments were relatively successful in laboratory mice, humans are not mice, and a whole new set of gene therapy strategies were needed. Fortunately, as a result of this intense research, gene therapy is enjoying a modern-day renaissance. Positive clinical results were observed in clinical trials in 2013 with patients with a blood cancer called acute lymphocytic leukemia, or ALL, and last year in patients an inherited form of blindness called choroideremia.

“We are somewhat late in the auditory field but I think we are getting there now,” said Tobias Moser of the University Medical Center Gottingen, Germany, who was not involved in the new research. “It’s an exciting time for gene therapy in hearing.”

Currently, there are no approved disease-modifying treatments for disabling hearing loss; a condition that affects 360 million people, or 5 percent of the world’s population, according to the World Health Organization. Hearing aids can amplify sounds, and cochlear implants convert sounds into electrical signals for the brain to decode, but such devices cannot fully replicate natural hearing.

The vast majority of hearing loss in older people (known as presbycusis) is noise-induced or age-related, but at least half of deafness that occurs before a baby learns to speak is caused by defects in one of more than 70 individual genes. These are the infants Swiss and U.S. researchers hope to help, after showing that replacing a mutated gene improved the function of hair cells of the inner ear and partially restored hearing in deaf mice.

Scientists from the Ecole Polytechnique Federale de Lausanne and the Boston Children’s Hospital tested hearing in newborn mutant mice by seeing how high they jumped when startled by a noise (startle response). Next, this team focused on a gene called Tmc1. Mutations in Tmc1 commonly cause human genetic deafness, and accounting for 4 to 8 percent of cases of inherited human deafness. But other forms of hereditary deafness can also potentially be “fixed” using the same strategy.

For those who are interested, the Tmc1 gene encodes a protein called Transmembrane channel-like protein 1 (TMC1), which is a membrane-embedded protein that is in the plasma membrane of Hair cells in the cochlea of the inner ear. TMC1 works with another membrane protein called TMC2 to interact with a protein complex called the “Tip link” proteins.

Tip Link Protein Complex

These Tip link proteins, protocadherin 15 and cadherin 23 help TMC1 and TMC2 to transmit signaling into the hair cell when it is deformed by sound waves in the cochlea. Without TMC1, the movements of the hair cells fail to generate any signal within it, and without internal signals, the hair cell will not send any signals to the auditory nerve.

Inner Hair Cells

Jeffery Holt and his colleagues used a small virus called adeno-associated virus (AAV) and genetically modified it so that it would carry the TMC1 gene. Next, they found that by using the promoter of the chicken β-actin gene, the TMC1 gene would be highly expressed in cochlear hair cells. When the inner ears of mice were infected with the TMC1-carrying AAVs, the deaf mice showed restored sensory transduction, auditory brainstem responses, and acoustic startle reflexes. This suggest that gene therapy with Tmc1 is well suited for further development as a treatment of auditory function in deaf patients who carry Tmc1 mutations.

Jeffrey Holt of Boston Children’s said their technique still needed work to perfect it, but he is very hopeful that clinical trials in human patients will start within five to 10 years.

Work at Novartis is more advanced, with the first patient treated last October in an early-stage clinical trial that will recruit 45 people in the United States, with results due in 2017.  The Swiss company’s product, acquired in a 2010 deal with GenVec worth up to $214 million, delivers a gene called Atoh1 that acts as a master switch for turning on the growth of inner ear hair cells that are central to hearing.

Drug Induces Hearing Restoration in Rodents

Fish and birds are able to regenerate their hearing after damage, but mammals are not able to do so, and hearing loss is irreversible in mammals like human beings. However, a new study has shown that the application of a particular drug can activate genes normally expressed during hair cell development. This work resulted from collaboration between researchers at Harvard Medical School, the Massachusetts Eye and Ear Infirmary, and Keio University School of Medicine in Japan. This finding is a first in the field or regenerative medicine.

Hair Cell Regeneration

In the cochlea, small cells known as hair cells convert sound waves into electrical signals that are interpreted by the brain into sounds. If these hair cells are damaged or destroyed by acoustic injury, then a permanent loss of hearing ensues. Such damage is treated with cochlear implants, which are surgically implanted devices that convert sounds to electrical signals.

“Cochlear implants are very successful and have helped a lot of people, but there’s a general feeling among clinicians, scientists, and patients that a biological repair would be preferable,” said Albert Edge, an otologist at Harvard University and the Massachusetts Eye and Ear Infirmary and lead author of the Neuron paper that reports these findings.

In previous work, Edge and his colleagues had shown that inhibiting the Notch signaling pathway was important for hair cells to form properly during fetal development (Jeon, S.J., Fujioka, M., Kim, S.C., and Edge, A.S.B. (2011). Notch signaling alters sensory or neuronal cell fate specification of inner ear stem cells. J. Neurosci. 31, 8351–8358). In their new study, Edge and his colleagues inhibited the Notch signaling pathway to determine, if such inhibition could initiate hair cell regeneration in adult mammals. They used a variety of approaches. In their first experiments, they used different inhibitors to determine their effects on isolated ear tissues. This allowed them to isolate one inhibitor in particular, the ɣ-secretase inhibitor LY411575, that led to increased expression of several molecular markers found in developing hair cells.


“It was quite a surprise,” said Edge. “We were very excited when we saw that a secretase inhibitor would have any effect at all in an adult animal.”

Next, Edge and his co-workers tested the inhibitor in mice that had hearing damage and reduced hair cell populations as a result of exposure to a loud noise. They tagged cells in the inner ear to follow their fate and discovered that the inhibitor, when applied to the inner ears of the mice, caused supporting cells to differentiate into replacement hair cells. These newly formed hair cells partially restored hearing at low sound frequencies, but not at higher frequencies. This effect lasted for at least three months.

This study examined the effect of the inhibitor when it was given one day after noise damage, which is a time when Notch signaling is naturally increased. This it is possible that a small window of time exists after an acoustic injury during which the drug is effective.

Edge concluded: “The improvement we saw is modest. So we’re now looking at variations of the approach and whether we can use the same drug to treat other types of hearing loss.”

See: Mizutari K, Fujioka M, Hosoya M, Bramhall N, et al. (2013) Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma. Neuron 77, 58-69.