Sensory hair cells in the cochlea of a Beethoven mouse treated with TMC2 gene therapy. In this confocal microscopy image, microvilli are shown in red and cell bodies in green. The human ear has about 16,000 sensory hair cells. [Charles Askew]
Sensory hair cells in the cochlea of a Beethoven mouse treated with TMC2 gene therapy. In this confocal microscopy image, microvilli are shown in red and cell bodies in green. The human ear has about 16,000 sensory hair cells. [Charles Askew]

Scientists have made another step forward toward delivering on the massive potential of gene therapy to reverse the underlying mutations that are the basis for various genetic disorders. Specifically, researchers from the Boston Children’s Hospital and Harvard Medical School have been able to restore hearing in mice with a genetic form of deafness, using a gene therapy approach. 

The investigators focused on a gene called transmembrane channel-like protein 1 (TMC1), which resides on the tip of hair cells within the cochlea. TMC1 forms a channel that allows calcium to enter the cell when moved by sound waves, inducing an electrical signal that is sent to the brain and interpreted as an auditory signal. The researchers chose TMC1, as it is a common cause of genetic deafness, accounting for close to 8% of cases.

“Our gene therapy protocol is not yet ready for clinical trials—we need to tweak it a bit more—but in the not-too-distant future we think it could be developed for therapeutic use in humans,” explained senior author Jeffrey Holt, Ph.D., associate professor of otolaryngology at Harvard Medical School.

The results from this study were published recently in Science Translational Medicine through an article entitled “Tmc gene therapy restores auditory function in deaf mice.”

Dr. Holt and his colleagues engineered an adeno-associated virus 1 (AAV1) to contain a functional copy of the TMC1 gene along with a promoter sequence, to make certain that the gene was turned on properly, and injected into the inner ear of two mouse strains. In one strain, the TMC1 gene was completely deleted and the other strain, the so-called Beethoven mice, contained single mutation within the TMC1 gene, rendering it ineffective. Both strains are good models for the dominant and recessive forms of TMC1 deafness within humans

After delivery of AAV1, the researchers tested the hearing of the mice by placing them into a “startle box”, where loud tones were administered and mice reactions are measured through a force plate on the floor beneath them. Remarkably, the scientists observed that both strains of mice were able to pick up the auditory signals. 

Additionally, the researchers noticed that the gene therapy treated mice began to detect sounds around the 80-decibel range, which is not typical for TMC1 mutants. “Mice with TMC1 mutations will just sit there, but with gene therapy, they jump as high as a normal mouse,” said Dr. Holt.

Ultimately, Dr Holt and his colleagues hope to partner with clinicians at Boston Children's department of otolaryngology and elsewhere to start clinical trials of TMC1 gene therapy within 5 to 10 years.

“Current therapies for profound hearing loss like that caused by the recessive form of TMC1 are hearing aids, which often don't work very well, and cochlear implants,” said Margaret Kenna, M.D., a specialist in genetic hearing loss at Boston Children's Hospital who is familiar with the current study. “Cochlear implants are great, but your own hearing is better in terms of range of frequencies, nuance for hearing voices, music and background noise, and figuring out which direction a sound is coming from. Anything that could stabilize or improve native hearing at an early age is really exciting and would give a huge boost to a child's ability to learn and use spoken language.”

The investigators believe that other forms of genetic deafness may also be amenable to the same gene therapy strategy, as severe to profound hearing loss in both ears affects 1 to 3 per 1,000 live births.

“I can envision patients with deafness having their genome sequenced and a tailored, precision medicine treatment injected into their ears to restore hearing,” Dr. Holt concluded.