AUDIOLOGY

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An “Old” Marketed Drug for T-Cell Lymphoma Restores Hearing in Mice

 

On October 6, 2006, the FDA granted regular approval to vorinostat (Zolinza(R); Merck & Co., Inc., for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies.

 

According to an article published online in Cell (28 June 2018), a novel drug therapy that partially restored hearing in mice, might shed light on molecular mechanisms of inherited form of progressive human deafness known as deafness, autosomal dominant 27 (DFNA27). The seed for this study was planted a decade ago, when the genomes of members of an extended family, dubbed LMG2, were analyzed. Deafness was genetically dominant in the LMG2 family, meaning that a child needs to inherit only one copy of the defective gene from a parent to have progressive hearing loss. The investigators then localized the deafness-causing mutation to a region on chromosome four called DFNA27, which includes a dozen or so genes. However, the precise location of the mutation eluded the research team.

 

A crucial clue to explain the DFNA27 form of progressive deafness arose from later studies of the mouse gene called Rest (RE1 Silencing Transcription Factor) when it was discovered that mouse Rest is regulated through an unusual mechanism in the sensory cells of the inner ear, and this regulation is critical for hearing in mice. Because the human counterpart of the mouse Rest gene is located in the DFNA27 region, the authors decided to rexamine the mystery of DFNA27 progressive deafness.

 

As a backgrounder, the coding sequence of a protein is generated from a gene by stitching together segments called exons while editing out the intervening segments. The resulting molecule serves as the template for a specific protein. Most previous studies had missed exon 4 in the Rest gene because this small exon is not edited into the Rest mRNA in most cells. The normal function of the REST protein is to shut off genes that need to be active only in a very few cell types. When the authors deleted exon 4 of Rest in mice, inner ear hair cells died, and mice became deaf. Many genes that should have been active were shut off in hair cells prior to their death. The team then pinpointed the deafness mutation in the LMG2 family and discovered that the mutation lies near exon 4, altering the boundaries of exon 4, and interferes with the inactivation of REST in hair cells. The authors then used Banfi’s exon 4-deficient mice as a model for DFNA27 deafness. Since REST suppresses gene expression through a process called histone deacetylation, they wanted to see if blocking this process could reduce hearing loss. Using small-molecule drug vorinostat, a HDAC inhibitor, it was possible to rescue the hearing of these mice.

 

According to the authors, these results demonstrate the value of studying the molecular mechanisms that underlie inherited forms of deafness, and that by following these genetic leads, it is possible to find novel and unexpected pathways that can, in cases such as this one, uncover unexpected potential treatment strategies in people.

 

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