Malaria medication can help people with hereditary hearing loss

June 12, 2019

Researchers have discovered that artemisinin, an antimalarial drug, could help patients with genetic or hereditary hearing loss. The results of the study were published in the latest issue of the journal. Proceedings of the National Academy of Sciences (PNAS). The study was entitledThe activation of unconventional secretory pathways restores the mechanotransduction of hair cells in a USH3A model. "

The Case Western Reserve University Medical School team used a zebrafish model to test whether the drug could be effective in hearing loss. They explain that hearing is due to the ability of certain proteins to reach the outer membrane of sensory cells present in the inner ear. They noted that artemisinin can help the inner ear to recognize and transport an important protein to the specialized cell membranes of the inner ear. These sensory cells contain projections resembling hair on the surface and are called "hair cells". The sound waves create vibrations that move the hairs of the cells. This motion signal is then converted into electrical signals that are transmitted to the brain that reads it as sound. These cells are therefore important, not only for hearing but also for balance.

The team explains that there is a mutant form of the essential protein called Clarin1 protein. This mutant form, unlike the normal version, can prevent the hair cells from transporting the protein to their membranes. This transport stop stops the hearing mechanism. Most clarin1 mutant proteins are thus trapped in the hair cells. This makes the cells incapable and these cells die quickly. In patients with Usher syndrome, there is a presence of this mutant or defective clarin1. This leads to a genetic hearing loss.

The team used a genetically modified zebrafish to obtain human versions of the mutant protein. It was then observed that artemisinin, an antimalarial drug, restored the function of the sensory cells of the inner ear. This led to the restoration of hearing and balance.

Lead author of the study, Kumar N. Alagramam, Ph.D., Chair of Research and Education Anthony J. Maniglia, and Associate Professor in the Department of Otolaryngology of the Faculty of Medicine. Case Western Reserve University Medicine, explained that his team has been working on this mutant protein for some time now. He said, "We knew that the mutant protein does not usually reach the cell membrane, except that patients with this mutation are born on hearing. This suggested to us that at least a fraction of the mutant protein had to reach the cell membranes of the inner ear. "

The team was looking for ways to secrete the mutant clarin1 to the membranes, says Alagramam, adding, "If we can understand how the mutant protein of human clarin1 is transported to the membrane, we can exploit this mechanism therapeutic."

The team then created genetically modified zebrafish models that replaced their genes for zebrafish clarin1 with human versions. Some have received human normal clarin 1 and other mutants that cause Usher syndrome in humans. Alagramam said: "Using these" humanized "fish models, we have been able to study the function of normal clarin and, more importantly, the functional consequences of its mutant counterpart. To our knowledge, it is the first time that a human protein involved in hearing loss is examined in this manner. "

The zebrafish modes were chosen for this study because they are easy to study and when they are in the larval stage, they are transparent. This helps to study the structure of the inner ear. The genes of this zebrafish that regulate hearing are also similar to those of humans, which has facilitated switching. The team used fluorescent labels on the proteins to track its movement in the hair cells of the zebrafish. Alagramam said, "To our knowledge, this is the first time that a mutant human protein badociated with hearing loss is 'escorted' through the pathway of unconventional cell secretion. This mechanism could provide a better understanding of the underlying process of hearing loss badociated with other mutant membrane proteins. "

They noted that the mutant clarin1 was trapped in the tubules of the cells. According to the team, if they could be released, it could result in a therapeutic benefit. To obtain it, they tried two different drugs: the thapsiggin (an anticancer drug) and artemisinin (an antimalarial drug). The results revealed that when the drugs were used, the trapped proteins were well released and the levels of clarin1 increased in the membrane. Overall, hearing and balance functions are also involved in processed zebrafish over untreated zebrafish.

The researchers found that balance was needed for the zebrafish to swim. Zebrafish with the mutant clarin1 were in staggering equilibrium until they were treated with artemisinin. The survival of fish depends on their ability to swim. Under artemisinin treatment, zebrafish survival rates increased from 5 to 45%, the researchers explained.

Alagramam said, "Our report highlights the potential of artemisinin to mitigate both auditory and visual losses caused by Clarin1 mutations. This could be a reusable drug, with a safe profile, to treat patients with Usher Syndrome. "