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New treatment strategy partially restores hearing in mice



Researchers have developed a small-molecule drug that partially restored a form of hearing loss in mice.

The inherited form of deafness -- called DFNA 27 -- was studied by researchers with the University of Iowa and the National Institutes of Health's National Institute on Deafness and Other Communication Disorders. Their findings were published Thursday in the journal Cell.

"We were able to partially restore hearing, especially at lower frequencies, and save some sensory hair cells," coauthor Dr. Thomas B. Friedman, chief of the Laboratory of Human Molecular Genetics at the NIDCD, said in a press release. "If additional studies show that small-molecule-based drugs are effective in treating DFNA27 deafness in people, it's possible that using similar approaches might work for other inherited forms of progressive hearing loss."

For more than a decades, NIDCD has been studying molecular mechanism of deafness, including the sensory hair cells.

"These results demonstrate the value of studying the molecular mechanisms that underlie inherited forms of deafness," Dr. Andrew J. Griffith, scientific director of the NIDCD, said. "By following these genetic leads, we find novel and unexpected pathways that can, in cases such as this one, uncover unexpected potential treatment strategies in humans."

About a decade ago, NIDCD researchers analyzed genomes of an extended family dubbed LMG2, in which deafness is genetically dominant.

The investigators found the deafness-causing mutation was in a region on chromosome four called DFNA27, which includes a dozen or so genes -- but they were not able to find the exact location.

Researchers at the University of Iowa later found a gene in mice that is regulated through sensory cells of the inner ear, which is critical for hearing. The gene was known as Rest -- or RE1 Silencing Transcription Factor.

Because the human counterpart is located in the DFNA27 region, the Iowa and NIDCD researchers resumed a study of DFNA27 progressive deafness.

When the researchers deleted the coding sequence called exon 4 in mice, inner ear hair cells died and mice became deaf. In addition, many active genes were shut off in hair cells before their death.

They found an alternative splicing of REST exon 4 regulates gene expression in hair cells. And the mutation lies near exon 4.

"We found that incorporating exon 4 into the REST mRNA acts like a switch in sensory hair cells," Banfi said. "It turns off REST and allows many genes to be turned on. Some of these turned-on genes are important for hair cell survival and hearing."

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