Usher syndrome type III (USH3) is an inherited condition that affects both vision and hearing. People with this syndrome are born hearing but during their lifetime, their hearing progressively deteriorates so that by middle age, they are profoundly deaf. USH3 is caused by a mutation in a gene called clarin-1. This gene carries the information to produce a protein that maintains the structural integrity of the hair cells in the ear, which are responsible for turning sound information into electrical signals that the brain can understand, and which are crucial for hearing.
People with USH3 are born hearing and only start to lose their hearing later in life (usually during their teenage years). This means there is a period of time, called a therapeutic window, where it is possible to treat the condition, and prevent the hearing loss before it starts. Researchers are developing treatments for USH3 that could be used in this therapeutic window. To test these treatments, they need animal models of the human condition, animals that develop progressive hearing loss like people with USH3. A team from Case Western Reserve University School of Medicine in Ohio, USA, led by Professor Kumar Alagramam, generated a model of USH3 by mutating the clarin-1 gene in mice. Like people with USH3, these mice developed a delayed progressive hearing loss. This is the first animal model of USH3 – this work was published in October in the journal “Scientific Reports”. You can read the original article here.
Professor Alagramam’s team genetically modified the mice so that clarin-1 protein was produced as normal in the hair cells during embryonic development, but then levels of the protein decreased after birth. This meant that the mice were born with normal hair cells and no hearing loss, but then developed a delayed hearing loss, that could be detected at 1 month of age (mice this age are equivalent to human teenagers). Using this new USH3 animal model, the researchers tested a gene therapy approach, in which a healthy copy of the clarin-1 gene was delivered into the hair cells, to try to restore the levels of clarin-1 protein in the cells. The results were very exciting, as they showed that treating mice with the gene therapy before they started to lose their hearing prevented the hearing loss. The team also showed that the treatment had to be administered before the hair cells started to degenerate, otherwise it was not possible to prevent the hearing loss in the mice.
This work has important implications for the development of treatments for USH3-associated hearing loss. Firstly, this new animal model of USH3 will allow other researchers to test how effective the treatments they are developing for USH3 are in preventing hearing loss. Secondly, this work has demonstrated that gene therapy may be a way to prevent hearing loss in people with USH3. Finally, if this gene therapy approach is approved for treating people in the future, it could be combined with genetic screening of newborn children. Genetic screening would allow clinicians to identify those children with clarin-1 mutations. This means they could then be given gene therapy to correct the mutation and prevent them from losing their hearing later in their life.