Genetic hearing loss may be reversible without gene
therapy
A large proportion of genetically caused deafness in humans may be
reversible by compensating for a missing protein, based on discoveries
in mice.
Emory University researchers have found that in mice, increasing the
amount of the protein connexin26 in the ear's cochlea compensates for an
absence of another protein, connexin30. The findings come 10 years after
scientists first discovered that connexin26 mutations cause much of the
deafness diagnosed at birth.
Xi (Erick) Lin, PhD, associate professor of otolaryngology and cell
biology at Emory University School of Medicine, was lead author of the
study, published recently in the Proceedings of the National Academy of
Sciences (http://www.pnas.org/cgi/content/full/104/4/1337).
"There are millions of deaf people affected by mutations in this
one gene, connexin26," he says. "Congenital hearing loss is
one of the most common human genetic birth defects, and that is why in
almost all the states universal newborn hearing screening is mandated by
law [including Georgia]."
In people without congenital hearing loss, connexin26 and connexin30
work together to form the cochlea's hybrid junction gaps, which
facilitate intercellular communication. But when one of the proteins is
missing, the hybrid junction gaps fail to work, and the cochlea's hair
cells die off, leaving the body incapable of translating sounds into
nerve impulses.
Even though scientists knew connexin26 was implicated in congenital
deafness, they did not know precisely why. Working with Emory colleagues
and scientists from the University of Bonn in Germany, Dr. Lin developed
contrasting hypotheses.
"The deafness could have two very different explanations,"
he says. "Either hybrid gap junctions have special biophysical
properties that cannot be replaced by gap junctions built with only one
type of connexin, or mutations in one of the two connexins just cut the
supply for making the gap junctions in half."
By adding extra connexin26 to mice that were missing connexin30, Dr.
Lin and his team proved the latter hypothesis. With the additional
connexin26, hearing sensitivity was restored and the expected hair cell
death never occurred. Those positive findings led Dr. Lin to conclude,
"The problem is simply caused by not having enough protein
remaining in the ear of these mutant mice to assemble gap
junctions."
Dr. Lin and his colleagues are now working to see if connexin-related
deafness can be reversed in a mouse model, or if increasing connexin30
may help when connexin26 is absent.
As the research picks up momentum, these results--and future
findings--may mean big changes for how congenital deafness is
approached. Up to now, says Dr. Lin, scientists working on hearing loss
had placed all their bets on gene therapy. That may no longer make
sense. "Gene therapy, which has very few successful cases so far,
may not be necessary," explains Dr. Lin.
Instead, Dr. Lin's findings indicate that a drug to boost connexin26
may be all that is needed. "Our work predicts that a drug should be
sufficient to cure connexin30 deletion-caused deafness," he says.
