Health Care

KU gene therapy holds new hope for restoring hearing

Researchers at the University of Kansas Hospital are using gene therapy to try to regrow the hair cells of the inner ear.
Researchers at the University of Kansas Hospital are using gene therapy to try to regrow the hair cells of the inner ear.

Amanda James first noticed a difference early this year when she picked up a pill bottle at the Norfolk, Va., pharmacy where she worked and shook it next to her right ear.

For the first time, she could hear the pills rattling inside.

James, 29, has been hearing impaired ever since she slipped into a swimming pool as a toddler and nearly drowned. The accident starved her of oxygen and obliterated the fragile microscopic hair cells of her inner ear that turn the motion of sound waves into nerve signals sent to the brain. She lost almost all the hearing in her right ear and retained just enough in her left ear to get by with a hearing aid.

But after receiving an injection directly into her right inner ear as part of a study at the University of Kansas Hospital, James seems to be slowly regaining some of the hearing she lost.

The results so far have been “amazing,” she said.

“It’s something new each month. I can hear music. I can hear your voice, but I can’t make out the words yet.”

About 36 million American adults have some form of hearing loss. For most, like James, it’s caused by the absence of inner-ear hair cells, an impairment called sensorineural hearing loss. For them, the options have been limited to just a few technological fixes.

People who retain some hearing can use hearing aids, sophisticated miniature amplifiers tuned to compensate for an individual’s lost sound frequencies. People with profound hearing loss can get cochlear implants, devices that surgically bypass the inner ear and provide a limited range of sounds directly to the auditory nerve to the brain.

But there has never been a way to actually restore hearing by regrowing the hair cells of the inner ear.

That’s where the research at KU comes in. The injection James received contains a gene that researchers hope will promote the growth of new hair cells. It’s had some success restoring hearing in mice. Now it’s being tried on a small number of people — the first time gene therapy has been used on people to restore hearing.

This clinical trial, which started at KU and has expanded to other medical centers, is being closely watched, hopefully but somewhat skeptically, by hearing researchers worldwide. It’s among the highest-profile projects in a field that recently has seen an outpouring of new research.

Researchers are looking at ways to protect hair cells from being damaged, to grow them in people with genetic conditions that leave them deaf at birth and to regrow the hair cells of people whose hearing has been impaired. Their work has caught the interest of drug companies trying to turn these findings into new therapies.

The Scientist, a bioscience magazine, recently counted at least six clinical trials underway on patients to test drug and gene therapies aimed at preventing or reversing hearing loss. The players include more than a dozen small biotech firms, as well as such big pharma corporations as Pfizer and Eli Lilly. Another giant, Novartis, is sponsoring the trial at KU.

“Drug companies had stayed away from (hearing restoration), but now they realize there’s a large market,” said Peter Barr-Gillespie, scientific research director of the Hearing Restoration Project of the Hearing Health Foundation. The project is a consortium of scientists from across the country who have been collaborating for several years on the basic research needed to understand how to regenerate hair cells.

“Hearing loss is the second most prevalent affliction, after anemia, worldwide,” said Barr-Gillespie, who also is a hearing researcher at Oregon Health & Science University. “People don’t realize how great the effect it has on your life, or how prevalent it is.”

Unlocking secrets

Hearing is an incredibly complex process performed by an organ that is packaged into an inner ear the size of a pinkie fingertip and locked away behind the hardest bone in the body.

Generations of scientists have been stymied in their attempts to determine the details of how it works and how to repair it when it’s damaged. Now, though, they’re taking advantage of many advances in genetics, neurology and biochemistry to unlock those secrets.

About 16,000 to 20,000 hair cells, along with larger numbers of supporting cells, are arrayed in clusters along the inner surface of the snail-shaped cochlea. Each cluster of hair cells along the spiral is tuned to a different frequency of sound. They’re bathed in a fluid that moves in response to the motion of sound waves. As the hairs move, they trigger nerve impulses that travel to the brain.

Some people have genetic conditions that keep their hair cells from ever developing. Accidents and illnesses, as well as some antibiotics and chemotherapy drugs, can destroy hair cells. The most common cause of hearing loss is prolonged loud noise, such as repeated explosions on a battlefield or high-decibel rock concerts, that can wipe out the cells.

While other animals, such as fish and birds, can regrow hair cells from their support cells, humans and other mammals cannot. Scientists don’t know why. It may be an ability that mammals lost somewhere along the evolutionary road.

The Hearing Restoration Project and other researchers have been looking at what genes are affected when hair cells are damaged for clues to how animals are able to regrow those cells.

For example, project researcher Tatjana Piotrowski of the Stowers Institute for Medical Research in Kansas City has been studying zebrafish. The fish have hair cells along the trunks of their bodies that sense movement of the water, a sign predators may be near. Piotrowski and her colleagues have discovered a way that the fish’s genes signal its support cells to grow into hair cells.

From such discoveries may come insights into what drugs might spur human support cells to become hair cells, Barr-Gillespie said.

He doesn’t want to hold out hope prematurely. When scientists discovered that birds can regenerate their hair cells, some were predicting human therapies within five years. That was about 30 years ago, he said.

Barr-Gillespie expects the Hearing Restoration Project to have “the bones of a strategy” within 10 years. And it will be years later until effective therapies are available. He is skeptical that the therapy KU is studying is it.

“That’s a big-deal trial,” he said. “At least it makes sense.” But he doesn’t think the therapy is “the magic switch and that’s it.”

The KU approach

The KU clinical trial relies on a gene called Atoh1, which is known to cause hair cells to generate in mammals while they are still embryos in the womb. Once enough hair cells develop, the gene is switched off, never to become active again.

“We artificially direct it to be on again,” said Hinrich Staecker, the KU researcher leading the clinical trial. “The idea is to kick-start the process that turns a supporting cell into a hair cell and then stop.”

The Atoh1 genes are packaged into a harmless version of a cold virus that can slip into the supporting cells to deliver the genes. Once inside, the genes order the supporting cells to start the process of growing into hair cells.

To get this therapy into a patient’s inner ear, Staecker makes an incision to open the eardrum and then uses a laser to drill a tiny hole into a bone that presses against the inner ear. Through that opening, he injects a tiny droplet, less than two-thousandths of an ounce, into the inner ear.

Since the clinical trial started in October 2014, Staecker has given the therapy to just six patients. A seventh has received it at Johns Hopkins School of Medicine in Baltimore and an eighth at Columbia University in New York City. The process has been slowed by the difficulty of recruiting patients who haven’t already received cochlear implants and by the study’s strict safety rules.

Using viruses to introduce new genes is an accepted technique. It’s been done safely in many clinical trials. But a well-publicized patient death in 1999 led to closer scrutiny of gene therapy. For this trial, each patient’s hearing and overall health must be thoroughly evaluated before Staecker can proceed to the next patient.

Staecker has been working on this therapy for about 16 years, conducting some of the initial studies on mice. These animals recovered about 50 to 70 percent of their hair cells, he said. By measuring the mice’s brain waves, the researchers found evidence that the animals also recovered hearing.

But how much hearing is an open question.

“We don’t really clearly understand how many hair cells you need to get X number of decibels of hearing,” Staecker said. “We don’t even know in animals.”

Staecker is hoping his patients recover enough hearing to make hearing aids a viable option. However, he is barred by Novartis from discussing the results so far from the clinical trial.

Jeff Bricker, 57, a cattle rancher in California, received the therapy in May in his right ear. He had been progressively losing his hearing in both ears since he was 12 years old.

“My experience with the procedure has been a mixed result,” Bricker said in an email.

“I have gained a few new hearing frequencies, so we know the process of nerve regeneration worked, but my speech comprehension has yet to show the results that we hoped for. It has been up and down. One month will show improvement and the next it will be down and then up again, so far. This has been frustrating for me, as the other participants in the study have done much better.”

Much work remains

Hearing researchers warn that there’s still much work to be done before hearing restoration becomes a reality.

“I wouldn’t call it insurmountable,” said Bernd Fritzsch, a hearing researcher at the University of Iowa. But there’s been “some degree of myopia” among researchers who examine one step toward restoring hearing without taking into account the steps that must follow. “We’re lulling ourselves into a simplicity” about how hearing can be restored.

The human ear, or any mammalian ear, may not be built to allow for the kind of tinkering that must be done to restore meaningful hearing, Fritzsch said.

For example, some researchers have had success growing hair cells from stem cells in the laboratory. But implanting those cells into the inner ear may be tricky, Fritzsch said, because there’s a fluid in the inner ear that’s toxic to all but the business end of the hair cells. To avoid being killed, the cells would have to be inserted very quickly into the inner-ear membrane, he said.

Fritzsch thinks the KU trial will be useful in determining whether gene therapy is safe when applied to the inner ear. Any hearing recovered by patients would be “frosting on the cake.”

Eventually, perhaps 10 years down the road, researchers may figure out a “cocktail of genes” that could be introduced into the inner ear to restore hearing, Fritzsch said.

“In the past, we were thinking of using one gene,” he said. But genes interact. “Atoh1 alone can’t do it. It needs partners.”

Staecker agrees that genes other than Atoh1 can be recruited to restore hearing. Eventually he hopes there will be a “whole armamentarium” of drugs. “This is not going to be the only thing for the inner ear.”

James is hoping her hearing will continue to improve. Voices still sound muffled and distant. She hasn’t regained enough of her higher frequencies to make them distinct. But she can pick them out when wearing earbuds.

“I appreciate what (hearing) I have.”

Now James has to tell her 4-year-old daughter and 7-year-old son to turn down the sound when they play on their iPad. And she’s trying to avoid using the alarm clock.

“It’s a most annoying sound.”

Alan Bavley: 816-234-4858, @AlanBavley

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