Investigating Gene Therapy for Hearing Loss

At a Glance

  • Most causes of hearing loss are due to the death of so-called inner ear hair cells, which detect sound waves and then send this information on to the brain.
  • The Department of Otolaryngology–Head and Neck Surgery at Columbia is one of three centers in the world conducting a gene therapy clinical trial in which cellular regeneration is being used to treat hearing loss.
  • The study involves an investigational drug containing a gene that has been shown to produce hair cells in pre-clinical trials.

“If we can intervene before the onset of the hearing loss, we could make a huge difference in patients’ lives. We are hopeful that this research will lead to treatment of patients with hearing loss of all types, possibly even supplanting the need for hearing aids and cochlear implants.”

— Dr. Lawrence R. Lustig

Hearing loss — acquired or genetic — is the most common sensory disorder in humans, with the majority of acquired hearing loss due to damaged or destroyed sensory hair cells in the inner ear.

“These tiny, critical cells allow us to convert sound vibrations of the natural world into the electrical impulse that goes to the brain,” says Lawrence R. Lustig, MD, Otolaryngologist-in-Chief at NewYork-Presbyterian/Columbia University Medical Center. He is also Chair of the Department of Otolaryngology–Head and Neck Surgery at Columbia University College of Physicians and Surgeons. “But once hair cells die — whether from trauma to the ear, aging, infection, noise exposure, or ototoxicity — they don’t grow back, and you permanently lose hearing capability.”

And therein lies the challenge for reversing hearing loss. At least until now.

The Department of Otolaryngology–Head and Neck Surgery at Columbia is one of three centers in the world conducting a clinical trial in which cellular regeneration is being used to treat hearing loss. For Dr. Lustig, this trial is the culmination of his interest and research in hearing loss that began while he was in medical school, where he took a year out of his studies to work in a research lab involved in the basic science around cochlear implantation. He ultimately followed this up with a fellowship and while as a faculty member at Johns Hopkins Medicine that allowed him to pursue research in basic auditory physiology. John Hopkins and the University of Kansas Medical Center are also participating in the trial, which is sponsored by Novartis Pharmaceuticals.

Dr. Lawrence R. Lustig

Dr. Lawrence R. Lustig

“The initial part of my research career at Johns Hopkins focused on understanding the basis of efferent neuronal transmission and outer hair cell function of the inner ear,” says Dr. Lustig, who is today one of the nation’s leading experts in hearing loss. Dr. Lustig’s work continued in earnest when he relocated to the University of California, San Francisco, to become its Chief of the Division of Otology and Neurotology. “We were looking at a particular protein called vesicular glutamate transporter 3 and found that it is integral to the development of hearing, while a mutation of the transporter causes early profound hearing loss.”

In follow-up studies, Dr. Lustig and his colleagues demonstrated that virally mediated gene therapy could successfully restore the hearing phenotype in a mouse model of genetic deafness. “In these surprisingly successful studies, we had the first model of inherited deafness in a mouse where we were able to rescue hearing essentially back to normal,” notes Dr. Lustig. “That led us to pivot our entire focus from basic science to translational projects attempting similar gene therapy rescue in other models of deafness.”

Paving the Way to Gene Therapy

“It was well-known for years that birds could regenerate hair cells, but mammals couldn’t,” notes Dr. Lustig. “In 1999, a group of researchers identified a particular gene – the atonal gene – in fruit flies followed by the creation of a mouse knockout of this gene. Everything else was totally normal in the ear, with the exception that they didn’t have any hair cells – either auditory or vestibular. That was the first clue that the atonal gene appeared to kick-start the supporting cells in the inner ear to become hair cells. Without that gene, no hair cells.”

sensory outer hair cells

Colored scanning electron micrograph of sensory outer hair cells from the organ of Corti, in the cochlea of the inner ear.

In 2005, researchers at the University of Michigan took this to a new and transformational level. They injected the mouse atonal (Atoh1) gene into a virus and then into the ear of a guinea pig.

“This was another first, showing that you could stimulate new hair cell growth in a living organism,” says Dr. Lustig. “They further validated this work with another study where they deafened the mice using the aminoglycoside antibiotic, which kills hair cells, and then added back in the Atoh1 gene on the adenovirus. They were not only able to demonstrate hair cell regeneration, but also some hearing recovery – the degree of recovery being related to the number of hair cells that regrew. This demonstration of functional recovery was a turning point in the field and generated a lot of excitement.”

Hinrich Staecker, MD, Ph.D., an otolaryngologist with the University of Kansas Medical Center then showed that you could do the same thing in the vestibular system using the same gene and virus.

“Over the next several years, research led by Dr. Staecker in collaboration with Novartis focused on developing a translational study using the human version of the gene – Hath1 – on an adenovirus backbone,” says Dr. Lustig. “This work led to the hair cell regeneration gene therapy trial now underway. This is the first cochlea gene therapy trial ever done in the ear – the first one in otolaryngology – so it’s revolutionary in that regard.”

Candidates for the study, which began recruitment in late 2014, must be totally deaf and well within cochlear implant candidacy range, says Dr. Lustig. “One of the challenges is finding patients who have that level of hearing loss who haven’t had a cochlear implant. Once you’ve had a cochlear implant you’re no longer a candidate for the study. Hearing loss also has to be in both ears. Patients who have lost all hearing in one ear and have good hearing in the other ear don’t qualify either – at least not yet. And candidates must have intact vestibular function in the nonoperative ear.”

Will the treatment that worked in the mouse improve hearing in humans and, if so, how long will it work — a few months, a lifetime? These are critical questions the trial seeks to answer.

“To deliver the therapy, we can either make a tiny little hole through the base of the stapes bone or do the injection through the round window membrane of the cochlea, a little membrane that we can access through the middle ear,” explains Dr. Lustig. “The delivery piece will not be the problem. The challenge is going to be developing the right vectors and the right genes and figuring out the best timing of treatment. If we can intervene before the onset of the hearing loss, we could make a huge difference in patients’ lives. We are hopeful that this research will lead to treatment of patients with hearing loss of all types, possibly even supplanting the need for hearing aids and cochlear implants.”

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