A widely-used anti-malaria drug may help prevent hearing loss caused by heredity and genetic disorders, a study has found. Researchers from Case Western Reserve University in the US conducted a study on zebrafish with a commonly used anti-malarial drug called artemisinin.
They found that the drug can help sensory cells of the inner ear recognise and transport an essential protein to the specialised membrane using established pathways within the cell, which will help improve and restore hearing. The ability to hear depends on these proteins reaching the outer membrane of the sensory cells in the inner ear which may be hindered due to certain types of mutations in the protein due to hereditary disorders, which prevent it from reaching those membranes.
The sensory cells of the inner ear are covered by hair-like projections, called hair cells, on the surface. These hair cells convert vibrations from sounds and movement into electrical signals that are conveyed through the nerves and translated in the brain into information for hearing and balance.
The genetic mutation of the protein -- clarin1 -- makes hair cells unable to recognise and transport the signals to the membrane and gets trapped inside the hair cells where they are harmful to the cells. This faulty secretion of clarin1 most commonly occurs in the Usher syndrome, which causes hearing and vision loss.
The study, published in the Proceedings of the National Academy of Sciences (PNAS), found that artemisinin restores cell function of the inner ear -- and thus hearing and balance -- in genetically engineered zebrafish that have human versions of the essential hearing protein. "We knew mutant protein largely fails to reach the cell membrane, except patients with this mutation are born hearing. This suggested to us that, somehow, at least a fraction of the mutant protein must get to cell membranes in the inner ear," said Kumar N Alagramam from Case Western Reserve University.
"If we can understand how the human clarin1 mutant protein is transported to the membrane, then we can exploit that mechanism therapeutically," Alagramam said. The team searched for any unusual secretion pathways mutant clarin1 could take to get to hair cell membranes and created several new zebrafish models where they swapped the genes encoding zebrafish clarin1 with human versions -- either normal clarin1 or clarin1 containing mutations found in humans with Usher syndrome.
"Using these 'humanized' fish models, we were able to study the function of normal clarin1 and, more importantly, the functional consequences of its mutant counterpart," said Alagramam. The study found that the majority of the mutant clarin1 got trapped in a network of tubules within the cell which helped proteins, including clarin1 to reach their destinations.
Based on this finding, they realised that liberating the protein from the tubules would be the solution they were looking for. After testing with different drugs, they came to the conclusion that artemisinin was effective in helping the mutant clarin1 to reach the membrane and improved hearing and balance.
"Our report highlights the potential of artemisinin to mitigate both hearing and vision loss caused by clarin1 mutations. This could be a re-purposable drug, with a safe profile, to treat Usher syndrome patients," said Alagramam.
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