This is a Fellowship Grant awarded to Dr Juan Fons at King’s College London in 2022.
Background
Otitis media (infection of the middle ear, sometimes called glue ear) is characterised by inflammation of the middle ear, an air-filled compartment between the eardrum and the inner ear. It contains three tiny bones, called ossicles, that transmit sound information from the eardrum into the inner ear. In most cases of otitis media, the infection is cleared easily from the middle ear. However, in some cases, the infection can become persistent, causing chronic inflammation of the middle ear. In these cases, fluid builds up in the middle ear and prevents the ossicles from moving freely. This in turn prevents sound information from being transmitted into the inner ear, causing a conductive hearing loss. In extreme cases, the bones can become damaged, the eardrum may burst or the sound-sensing hair cells in the inner ear may be damaged. Affected people often experience significant pain, and in some cases their hearing loss may become permanent.
People with Down syndrome are especially susceptible to developing chronic otitis media. By 1 year of age, over 90% of people with Down syndrome will have had at least one middle ear infection. Around 10-20% of adults with Down syndrome have hearing loss caused by these infections, affecting their communication and social integration. We do not know why people with Down syndrome are at increased risk of developing these chronic middle ear infections.
Current treatments for chronic otitis media are antibiotics and surgery to insert a tube, or grommet, through the eardrum to allow the fluid to drain from the middle ear. However, although these treatments relieve the symptoms, the effect is often temporary, with antibiotics being unable to fully clear the infection and people often having to undergo repeated surgeries. There is currently no permanent and fully effective treatment.
Aim
In this project, Juan will investigate the causes of otitis media in people with Down syndrome. He will focus on a gene called Dyrk1a in his project – evidence suggests that this gene is involved in the development of the middle ear. As people with Down syndrome have three copies of this gene, instead of the more usual two, it may underlie their increased susceptibility to middle ear infections.
One of Juan’s collaborators has generated mouse models of Down syndrome, and Juan will study these mice with a particular focus on the Dyrk1a gene and its role in susceptibility to chronic otitis media. Juan will study how the middle ear develops differently in these mice compared to ‘normal’ mice. He will also investigate how the increased gene activity caused by having three, rather than two, copies of the gene leads to chronic otitis media.
As part of his project, Juan will test several existing drugs for their ability to prevent or treat otitis media in the mouse model of Down syndrome. He will measure how effective these drugs are in correcting the activity of the Dyrk1a gene and thus preventing or treating chronic otitis media. This could be the first step towards developing them as a treatment for use in people.
Benefit
This project will improve our understanding of why people with Down syndrome are at higher risk of chronic middle ear infections and the hearing loss that they cause. It may also provide the first step towards an effective treatment, avoiding the use of repeated surgeries. It will also improve our general understanding of middle ear development and the processes involved when middle ear infections become chronically persistent.