STOCK.XCHNG, DJEYEWATERSensory disorders can have a profound effect on health and quality of life—but gene therapy may be coming to the rescue. Gene therapy’s success in treating blindness disorders –many are in late stage trials—gave hope to a field deterred by early missteps. And now gene therapy researchers are expanding their gaze to focus on all manner of sensory diseases.

In the last year, researchers have demonstrated successes in using gene therapy to restore function in mice that have lost the ability to hear and smell. Other teams are tackling pain management via gene therapy, hoping to overcome the ever-present problem of opioid tolerance. Some of these therapies are already beginning human trials, and as the challenges of injecting viral vectors and genetic materials into patients are overcome, researchers argue that it may one day be possible to treat anything from deafness to anosmia with a simple injection.


One notable success in using gene therapy techniques to treat a sensory disorder came last year when otolaryngolotist Lawrence Lustig at the University of California, San Francisco, and colleagues helped deaf mice hear again. Glutamate is a neurotransmitter important for connecting the inner ear hair cells that respond to sound vibrations with the auditory neurons that carry those signals to the brain. Indeed, a missense mutation in the vesicular glutamate transporter-3 (VGLUT3) gene, which is responsible for releasing the neurotransmitter glutamate from hair cells has been linked to a progressive form of human deafness. Working with mice carrying a defect in VGLUT3, Lustig’s team restored some function to hair cells of mutant mice by expressing the VGLUT3 protein.

“The neurons [in VGLUT3 mutant mice] are waiting for the neurotransmitter to activate them”—but no signal comes, and the mice are profoundly deaf, Lustig explained. But when the scientists treated VGLUT3 mice with gene therapy carrying the unmutated gene, their neurons fired again, and their startle responses to sudden noises recovered to about a third of normal mice.  

Lustig thinks the results are promising, and is “working on more broadly applying [the therapy] to other forms of genetic hearing loss,” he said. But in contrast to VGLUT3 mutant mice, which are missing the protein entirely, humans with missense mutations expressed a defective transporter, making it unclear whether Lustig’s strategy could translate to human VGLUT3-linked deafness.

Other researchers are looking into whether gene therapy could be used to aid current deafness treatments—namely, cochlear implants. Deafness is often caused by lost or damaged hair cells that cannot relay signals to auditory neurons. In such cases, cochlear implants may be used to respond to sound and transmit electrical signals to the nerve cells. But these neurons often degenerate and retract from the cochlea as fewer growth factors are released by impaired hair cells.

In 2012, a team led by Yeohash Raphael, an inner ear biologist at the University of Michigan, designed a gene therapy to prevent auditory neuron degeneration in experimentally deafened guinea pigs whose inner ear hair cells had been destroyed by neomycin injection. The researchers used a viral vector to stimulate the guinea pigs’ inner ear epithelial cells to produce a neurotrophic growth factor, prompting auditory nerves to sprout into the cochlear epithelium despite the lack of input from hair cells.

Because the guinea pigs have no hair cells, “the treatment will not give hearing [on its own],” noted Raphael. But enabling auditory nerves to grow closer to a cochlear implant should help the prosthesis transmit signals to the neurons and increase its success.

The smell of success

Taste and smell are two of the senses that have received less attention from gene therapy researchers—but that’s changing. Just last fall, researchers at the University of Michigan restored the sense of smell to mice with a genetic defect causing anosmia.

“In olfactory dysfunction, there are few curative therapies,” said pharmacologist Jeffrey Martens, who led the study. In most cases, olfactory cilia—important structures for transmitting signals from odor molecules to olfactory neurons—are damaged by aging or trauma. But some anosmias are caused by genetic defects.

Martens’s team studied the Oak Ridge Polycystic Kidney (ORPK) mouse strain, which carries a mutation in the gene for IFT88, a protein critical to cilia structure. Cilia are important in various organs, including the kidney, and the mice are generally studied as a model for polycystic kidney disease. But the researchers found that ORPK mice also have fewer and malformed olfactory cilia and that young ORPK mice were undersized compared to normal mice—implying that odor-guided behaviors like feeding might be disrupted.

Treating the mice intra-nasally with gene therapy vectors carrying the wildtype Ift88 gene, researchers saw significant regrowth of nasal cilia, whereas control mice given empty vectors showed no regrowth. Treated mice almost doubled in weight compared to controls.

Demonstrating that gene therapy can rescue defects in one ciliopathy model bodes well for the third or more of olfactory dysfunctions due to congenital ciliopathies, Martens said. The research also offers hope for treating cilia-related disorders in other organs, including the kidney and retina, he added.

A taste for a new treatment

So far, no scientists have designed a gene therapy to target taste buds, but at least one team is tackling an important factor in taste: saliva. If a person’s saliva production drops below 50 percent of normal, “you get tooth decay and trouble swallowing,” explained Bruce Baum, a dentist and molecular physiologist recently retired from the National Institute of Dental and Craniofacial Research. And without saliva to dissolve taste molecules, “you don’t taste as well either,” he added.

Most people never experience more than the occasional dry mouth, but loss of salivary gland function is a grim reality for many head and neck cancer patients, who undergo cancer-treating radiation that is deadly to the salivary glands’ acinar cells. When radiation destroys too many of these cells, which are responsible for releasing the water that composes saliva, drugs to boost saliva output do little good.

Baum and his colleagues decided to make other salivary gland cells—called duct cells—into saliva-producing cells by prompting them to express a water channel-forming protein called aquaporin. In 2012, the researchers reported on a Phase 1 clinical trial in 11 patients who’d previously been radiated for head and neck cancers. Baum and his colleagues found that 42 days after infusing the aquaporin-containing viral vector into one salivary gland per patient, six patients had increased saliva flow, and five of these felt that their symptoms of dry mouth had abated. The patients are still being followed to determine how long saliva output remains elevated.

More work is needed to optimize the strategy, but Baum noted that the first clinical trial “was a reasonable strategy to show people a quality of life disorder can be addressed with so-called ‘new fangled’ therapies.”

Soothing touch

Scientists are also developing gene therapies for disorders involving touch—or at least pain-sensing—neurons, with one drug candidate already through a Phase 1 trial. The strategy uses a replication-defective herpes simplex virus (HSV) vector, which in its natural form causes cold sores, to express the body’s own pain-killing chemicals in nerve cells.

Patients often become tolerant to prescription opioids like morphine, needing higher doses to relive pain, explained Darren Wolfe, a molecular geneticist turned CEO of PeriphaGen. But by targeting analgesic compounds to specific neurons near pain centers, Wolfe and his collaborators hoped they could use low doses to ameliorate pain and prevent drug tolerance. In a Phase 1 trial published in 2011, the team treated 10 terminal cancer patients with intractable pain with a similar HSV vector carrying the gene for the pain-killing molecule preproenkephalin. The six patients receiving the two highest doses reported that their pain dropped by 80 percent within 2 weeks after receiving treatment, and a follow-up Phase 2 trial is planned.

PeriphaGen is also gearing up for a Phase 1/2 trial of a vector carrying the gene for the neurotransmitter gamma-aminobutyric acid (GABA), to treat diabetic neuropathy, the painful burning and tingling sensation often experienced as nerves are damaged in chronic diabetes. Wolfe envisions that someday pain treatment could be as simple as visiting the doctor every few months for a quick skin prick “wherever it hurts”—choosing between a variety of genes to get the best effect.

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