November 22, 2011

Reversing Deafness with Gene Therapy

(Ivanhoe Newswire) — Mutated genes in the sensory hair cells of the inner ear prevent sound waves from being converted into electrical signals- a fundamental first step in hearing. Restoring electrical signals in the sensory cells of deaf mice by introducing new genes allowed the mice to hear.

The study paves the way for a test of gene therapy to reverse a type of deafness.

Sound waves produce the sensation of hearing by jiggling protruding hair-like structures on sensory hair cells in the inner ear. Scientists have long believed that the hair cells carry a protein that converts this mechanical motion into electrical signals. While similar proteins have been identified for other senses — taste, smell, sight — researchers had been unable to find the critical protein required for hearing, in part because of the difficulty of getting enough cells from the inner ear to study.

"People have been looking for more than 30 years," Jeffrey Holt, PhD, in the department of otolaryngology at Children's Hospital Boston, was quoted as saying. "Five or six possibilities have come up, but didn't pan out."

Holt, Andy Griffith and colleagues found that two related proteins, TMC1 and TMC2, are essential for hearing. They make up gateways known as ion channels, which sit atop the hair-like projections (called stereocilia) and let electrically charged molecules (ions) move in to the cell, generating an electrical signal that ultimately travels to the brain.

The gene for TMC1 was previously shown by Griffith and NIDCD-funded collaborators to be mutated in both mice and humans with hereditary deafness. TMC2, the new study found, seems to have a redundant function and may compensate if TMC1 is defective.

The study also found that the same defects affect sensory hair cells in the vestibular system, which underlies the sense of balance. Although TMC1 mutations cause only hearing loss, not balance problems, in humans, mice with defects in both TMC1 and TMC2 are deaf and fail balance tests requiring them to navigate a rotating rod.

The investigators then engineered an adenovirus to carry normal copies of TMC1 or TMC2 into the inner-ear hair cells of mice that had mutations in both genes. Using special techniques developed in Holt's lab, they recorded electrical responses to noise in the sensory hair cells when either TMC1 or TMC2 was added back — where before there had been none. "This is the first time anything like this has been done," said Holt.

SOURCE: Journal of Clinical Investigation, published online November 21, 2011