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When a small cluster of biotechs working on drugs for hearing loss cropped up in the Boston area several years ago, it raised the hopes of legions of mostly older people who rely on hearing aids or implanted electronic devices.

Since then, investors have poured hundreds of millions of dollars into those local startups. The young companies have snapped up top scientists and genetic experts from Harvard, MIT, and Massachusetts Eye and Ear. And Greater Boston has emerged as the hub of hearing restoration efforts.

All the elements are in place for a breakthrough. But therapies to regenerate lost hearing — rather than simply amplify sound — still may be years away.

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It’s the classic biotech conundrum, familiar to those targeting hard-to-treat diseases ranging from cancers to dementia. Even with big demand, high hopes, and ample funding, the hurdles remain formidable. And the scientific and regulatory journeys almost always take longer than anticipated.

“People think a drug could be ready in about five years,” said Dr. Bradley Welling, a neurotologic surgeon at Mass. Eye and Ear who tracks the research closely. He said he sees genuine progress but, almost apologetically, added a cautionary note: “That’s what they also said five years ago.”

Early-stage research and clinical trials have shown encouraging signs, along with some stumbles. But after false starts and experimentation, three of the largest biotech players — Frequency Therapeutics, Decibel Therapeutics, and Akouos — have settled on approaches they think offer the best hope to restore lost hearing: gene therapy and regenerative medicine. They’re also among the most scientifically challenging approaches.

“We see this as a new mode of medicine,” said David Lucchino, chief executive of Woburn-based Frequency, which uses technology discovered by noted Cambridge scientists Robert Langer and Jeffrey Karp “It’s about working with the body’s natural regenerative system to heal itself.”

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In essence, they are trying to plant in the damaged inner ear healthy genes that regulate hearing and balance or molecules that can activate dormant hair cells to regenerate hearing. The challenge is not only to develop the right formulation but also find a way to surmount what’s called the blood-cochlear barrier. This protects the inner ear from toxins in the bloodstream but also makes it harder for drugs to penetrate.

There are currently only a small number of approved gene therapies on the market in the United States, including one for a rare eye disease and one for spinal muscular atrophy. Both use benign viruses known as “viral vectors” as delivery vehicles. Some of the biotechs are looking into whether this technique could also be used in the ear drum.

For many whose hearing has deteriorated, or who were born with genetic defects, the first genetic therapies can’t come too soon.

“Anything to get my hearing back to a level where I can have a normal conversation would be wonderful,” said retired systems analyst Mark Filteau 69, who grew up in Fitchburg but now lives in Orlando and wears hearing aids.

Drug makers are eyeing a potential market of half a billion people worldwide — an estimated three quarters of them older people struggling to talk to family or friends or to hear ringing phones or doorbells. Many are aging baby boomers who sat too close to the speakers at rock concerts, wielded jackhammers on construction sites, or worked in engine rooms or on airport runways.

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“It’s one of the largest unmet needs in medicine,” said Manny Simons chief executive of Akouos, which recently moved 53 employees into a former art warehouse overlooking the Reserved Channel in South Boston. The company has raised $57 million to bankroll a gene therapy that would initially treat children who were born deaf but could eventually target a much broader population.

One sign of the keen investor interest is the trajectory of Frequency, one of the first hearing startups out of the gate. The company, with 55 employees, raised $84 million when it went public last fall after posting promising data from an early clinical trial. Its market value is close to $700 million.

Frequency gained wide attention last year when a small number of adults with the most common form of hearing loss showed modest improvements in hearing range and word recognition tests after a two-drug combo was injected into their ear drums in gel form. Its experimental therapy seeks to help generate hair cells in the inner ear. The company is now enrolling 96 patients in a larger trial at a dozen US sites.

Another early player, venture-backed Decibel, recently scrapped research programs exploring other approaches, laying off an unspecified number of employees. The company last week said it has narrowed its focus to regenerative medicine, initially for age-related balance disorders associated with hearing loss. It also said its founding chief executive, Steven Holtzman a biotech veteran, was retiring.

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“We’re committed to being a hearing loss and balance company and we’re doubling down on regenerative medicine,” said new Decibel chief executive Laurence Reid, who previously led Warp Drive Bio.

Decibel, based across the street from Fenway Park, has raised more than $100 million and now has 45 employees. In addition to its treatment for balance disorders, it’s still working on two other drug candidates: one to prevent hearing damage in cancer patients receiving a chemotherapy, the other to improve hearing to people born with hearing loss due to a gene mutation.

Another player, Audion Therapeutics, though based in Amsterdam, conducts research in the LabCentral complex in Cambridge. It’s working on a way to inhibit a protein that prevents hair cells from regenerating, using a technique developed at Mass. Eye and Ear. Other companies are working outside Boston: Swiss pharma giant Novartis has been testing a treatment, and the field has attracted a pair of West Coast startups, Otonomy of San Diego and Sound Pharmaceuticals of Seattle.

Hearing-impaired Americans who are tracking the developments believe “it’s a matter of when, not if,” said Barbara Kelly, executive director of the Hearing Loss Association of America, a patient advocacy group in Washington. “Science is advancing, and the future of what they’ll be able to do is amazing.”

But not all are certain they would try a genetic treatment.

“I might be interested in exploring a therapy,” said Jack Murray, 71, a Providence retiree who started having trouble hearing high frequencies about 15 years ago and now wears hearing aids. “But I’d want to know about potential side effects before I did. I can live with what I have.”

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Others are living with hearing aids or cochlear implants but not always happily. Many say they increase the volume, but not the clarity of sound.

Bedford retiree Mary Drake, 75, bought her first set of hearing aids in her mid-60s. “I was in denial,” she said. “My husband said, ‘If the television gets any louder, the people downstairs are going to complain.’”

For Drake, who said her hearing aids have helped her but “aren’t perfect,” the prospect of a genetic therapy would be a no-brainer.

“I’m open to anything," she said. "I’d offer myself up as a guinea pig.”


Robert Weisman can be reached at robert.weisman@globe.com. Follow him on Twitter @GlobeRobW.