Richard Smith, M.D., the Sterba Hearing Research Professor in Otolaryngology at the UI Roy J. and Lucille A. Carver College of Medicine, described the study as a proof-of-principle experiment, but added that the success may point the way to new treatments for deafness in humans.
"We gave a genetically-deafened mouse interfering RNA that specifically prevents a gene from being expressed that would otherwise cause deafness. By preventing its expression, we prevented the deafness," said Smith who was senior author of the study. "Even though this is in the early stages, it is really exciting because it points to other options for people who have hearing loss other than hearing aids or cochlear implants."
The gene-silencing technique used by the UI team is called RNA interference (RNAi) and works specifically against genetic conditions caused by a so-called dominant negative mechanism -- when a single copy of the mutant gene is sufficient to cause disease because the protein from the faulty gene has a dominant adverse effect over the protein from the normal gene. Although many of the most common deafness genes do not work through this mechanism, several human forms of inherited deafness, including the one mimicked by the UI mouse model, are caused by a dominant negative mechanism.
To test the gene-silencing technique, Yukihide Maeda, M.D., Ph.D., a postdoctoral researcher in Smith's lab and lead author of the study, introduced a mutated gene that causes deafness in humans into the inner ear of mice. This gene acted through a dominant negative mechanism, and the mice had moderate hearing loss. Next, Maeda simultaneously introduced the mutant gene and a short piece of interfering RNA specifically designed to silence the gene. Standard hearing tests, similar to those used on newborn babies, confirmed that the treated mice were able to hear.
Smith noted that RNA interference was not only successful but also highly specific. Despite the fact that the mouse and the human gene differed by only two nucleotides over the short stretch of gene targeted by the RNAi, the mutant human gene was silenced while the normal mouse gene was unaffected.
With a view to someday moving this therapy to humans, the researchers also developed a non-invasive strategy to deliver the RNAi. A small piece of foam soaked in a solution containing the interfering RNA was placed against the membrane covering one opening into the inner ear of the mice. The slightly porous membrane allowed the interfering RNA to diffuse into the inner ear cells.
Although the UI team was successful in curing the mice of their genetic deafness, and the delivery strategy should translate easily to humans, a number of issues still must be addressed before the technique can be considered as a potential human therapy. These hurdles include determining if the treatment will still work in a mouse that has been deaf for some time before the RNAi is delivered, and finding ways to sustain the gene-silencing effect over an extended period of time.
Smith added that developing the technique to produce long-term rescue of hearing loss is a future focus for his research team.
In addition to Smith and Maeda, the research team included Kunihiro Fukushima and Kazunori Nishizaki of Okayama University Graduate School of Medicine in Okayama, Japan. The study, which was published in the June 15 issue of Human Molecular Genetics, was funded by the National Institutes of Health.
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Human Molecular Genetics