A gene therapy recently won Food and Drug Administration approval as a treatment for a specific form of hereditary hearing loss. Wade Chien, a Johns Hopkins researcher and clinician, performed foundational research that was part of this collective effort to move gene therapy from the bench to the bedside.

Chien, a fellowship-trained professor of otolaryngology–head and neck surgery at Johns Hopkins, also leads the Section on Inner Ear Therapeutics at the National Institutes of Health’s National Institute on Deafness and Other Communication Disorders.

His lab was one of the first to show that adeno-associated viruses could act as delivery systems to bring unmutated genes to the inner ear to replace defective ones. “If you have a mutation in a particular gene that’s important for hearing, we can potentially use viruses to deliver the normal copies of that gene into the inner ear to restore hearing,” he says.

His 2017 study used this method to improve hearing and balance in mice that had been genetically modified to develop a rare form of Usher syndrome called USH2D. These mutant mice lack an important protein called whirlin, which is needed for the development of hairlike projections called stereocilia, which protrude from the inner ear sensory hair cells. The therapy delivered a corrected version of the whirlin gene, which caused whirlin protein to be expressed in the sensory hair cells, thereby restoring their function.

“Since our early work, this concept has been successfully implemented in many different mouse models of hereditary hearing loss and dizziness,” he says.

The FDA in April approved a therapy for a rare type of hereditary hearing loss called DFNB9, which is caused by mutations in a gene known as OTOF. Children with DFNB9 are characterized by severe-to-complete congenital deafness. After gene therapy treatment, many of these patients were able to hear for the first time in the treatment ear. It is the first gene therapy approved for hereditary hearing loss.

Chien’s lab remains focused on developing therapies to help patients born with genetic mutations identified as causing hearing loss. About 150 hearing-loss-associated genes have been identified to date, he says.

He works closely with researchers who modify the viruses to target specific cells, such as the sensory hair cells in the inner ear. “In order for the therapy to be effective, you need the right delivery vehicle, so your therapy is delivered to the right cells,” he notes.

An important part of Chien’s research is determining the optimal delivery method, dosages and developmental timing. “In mice — and in humans, too — the inner ear is a very small organ. The hearing and balance systems in the inner ear start to develop before birth,” he says. “We want to make sure that the therapy is going to be able to perfuse through the inner ear to safely and efficiently get to the targeted cell types in the inner ear at the right time.”

Chien says over half of children born with hearing loss have a genetic component as the cause.

He became interested in gene therapy when he began practicing as an otolaryngologist and saw that these children had few options beyond hearing aids and cochlear implants. Though these technologies have progressed, he says, patients often find the equipment uncomfortable or unsatisfying, particularly in noisy settings or when listening to music. 

“I thought that perhaps we could try to develop better therapies to help these patients,” he says. “The main focus of our lab is to try to develop therapies to help these children.”