A research project at Kansas State University has potential to treat human deafness and loss of balance.
More than 28 million people in the United States suffer some form of hearing loss and mutation of the SLC26A4 gene, normally found in the cochlea and vestibular organs of the inner ear as well as in the endolymphatic sac, a non-sensory part of the inner ear, is implicated as one of the most common forms of hereditary hearing loss in children worldwide.
When the mutant mice lack SLC26A4 expression, their inner ears swell during embryonic development. This leads to failure of the cochlea and the vestibular organs, resulting in deafness and loss of balance.
"When the SLC26A4 gene is mutated, it leads to a loss of pendrin expression, which causes swelling of the inner ear and loss of hearing and balance," said co-author Philine Wangemann, Kansas State University distinguished professor of anatomy and physiology. "In my research, I have been interested in how the inner ear functions. We worked on the idea that if you keep one domino in the chain standing, then the others would continue to stand and function normally. In other words, if we could restore the proper expression of pendrin in the endolymphatic sac and thereby prevent swelling of the sac, this may prevent swelling of other parts of the inner ear and rescue hearing and balance."
The multitude of sites where SLC26A4 is located made the goal to restore function look futile, unless some sites were more important than others.
Schematic diagram of the inner ear. A) Diagram of the membranous labyrinth. The two continuous luminal fluid spaces of the mature inner ear are filled with endolymph (pink and purple). B–E) Diagrams of a cross section of one cochlear turn (B), of the utricle or saccule (C), of one ampulla (D) and the endolymphatic sac (E). Cells that express pendrin (yellow cells pointed to by arrows) are diagrammed in mature tissues. Credit: doi:10.1371/journal.pgen.1003641.g001
"We generated a new mutant mouse that expresses SLC26A4 in the endolymphatic sac, but not in the cochlea or the vestibular organs of the inner ear," Wangemann said. "Fantastically, this mouse did not develop the detrimental swelling of the inner ear and even more exciting, the mouse developed normal hearing and balance."
That restoration of hearing and balance lasted for the duration of the testing period, which suggests that the restoration is permanent.
"Our study provides the proof-of-concept that a therapy aimed at repairing the endolymphatic sac during embryonic development is sufficient to restore a lifetime of normal hearing and balance," Wangemann said.
While these findings are made in a mouse model, Wangemann said that eventually the idea is to develop a pharmacological treatment for human patients, but much more research will be necessary, such as to understand how fluid secretion and absorption is supported and how the balance of secretion and absorption is maintained to prevent the detrimental swelling.
Citation: Xiangming Li, Joel D. Sanneman, Donald G. Harbidge, Fei Zhou, Daniel C. Marcus, Philine Wangemann , Taku Ito, Andrew J. Griffith, Raoul Nelson, Nicolas Picard, Régine Chambrey, Dominique Eladari, Tracy Miesner, SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice. PLoS Genet 9(7): e1003641. doi:10.1371/journal.pgen.1003641