A step closer to gene therapy that restores hearing for congenitally deaf

A step closer to gene therapy that restores hearing for congenitally deaf
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Findings from a new study have brought the possibility of gene therapy that could restore hearing in the congenitally deaf one step closer.

Mutations in the inner-ear protein coding gene otoferlin are linked to severe congenital hearing loss, however, the gene is too big to package into a delivery vehicle for molecular therapy. Now, a team of researchers from Oregon State University is exploring using otoferlin in a shortened form to use for this therapy.

The findings have been published today in Molecular Biology of the Cell.

Gene mutations

Associate professor of biochemistry and biophysics in the OSU College of Science, Colin Johnson, graduate student Aayushi Manchanda, and their team have demonstrated that the shortened version of otoferlin needs to include a part of the gene known as the transmembrane domain as without it the sensory cells were slow to mature.

“For a long time otoferlin seemed to be a one-trick pony of a protein,” said Johnson. “A lot of genes will find various things to do, but the otoferlin gene had appeared only to have one purpose and that was to encode sound in the sensory hair cells in the inner ear. Small mutations in otoferlin render people profoundly deaf.”

“That was surprising since otoferlin was known to help encode hearing information but had not been thought to be involved in sensory cell development.”

In 2017, Johnson’s lab identified a truncated form of the gene that can function in the encoding of sound. To test whether the transmembrane domain of otoferlin needed to be part of the shortened version of the gene, Manchanda introduced a mutation that truncated the transmembrane domain in zebrafish, which share a remarkable similarity to humans at the molecular, genetic, and cellular levels.

“The transmembrane domain tethers otoferlin to the cell membrane and intracellular vesicles but it was not clear if this was essential and had to be included in a shortened form of otoferlin,” Manchanda said. “We found that the loss of the transmembrane domain results in the sensory hair cells producing less otoferlin as well as deficits in hair cell activity. The mutation also caused a delay in the maturation of the sensory cells, which was a surprise. Overall, the results argue that the transmembrane domain must be included in any gene therapy construct.”

At the molecular level, Manchanda found that a lack of transmembrane domain led to otoferlin failing to properly link the synaptic vesicles filled with neurotransmitter to the cell membrane, causing less neurotransmitter to be released.

“Our study suggests otoferlin’s ability to tether the vesicles to the cell membrane is a key mechanistic step for neurotransmitter release during the encoding of sound,” Manchanda added.

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