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Malaria Drug Could Moderate Genetic Hearing Loss

Guerra, Alexis

doi: 10.1097/01.HJ.0000575364.22209.74
Genetic Hearing Loss
Free

Alexis Guerra is a third-year journalism student at Quinnipiac University and is completing her internship with The Hearing Journal. She is the managing editor of her campus newspaper, Quinnipiac Chronicle. Writing has always been her passion and she hopes to continue working in the journalism industry.

A recent study, titled “Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model,” provides evidence that may help patients with genetic or hereditary hearing loss. Using a zebrafish model, researchers at Case Western Reverse University (CWRU) School of Medicine found that the anti-malarial drug artemisinin is a potential solution to hereditary hearing loss. The ability to hear relies on proteins to reach the outer membrane of sensory cells in the inner ear. However, when there are mutations in the protein, as found in certain types of hereditary hearing loss, it is prevented from reaching these membranes that are vital for hearing and balance. Instead, most mutant proteins, called protein-clarin1, get trapped within the hair cells which causes them to become ineffective and unable to survive. This mutant protein is present in patients with Usher syndrome, which leads to genetic hearing loss.

To conduct their research, the team used genetically engineered zebrafish to have human versions of the mutant protein. Artemisinin was then seen to restore the inner ear sensory cell function, which led to the restoration of both hearing and balance. Lead author of the study, Kumar N. Alagramam, PhD, and his team have been working on this mutant protein for some time now, knowing that the mutant protein fails to reach the cell membrane, except in patients with the mutation who are born able to hear. This led his team to believe that, somehow, at least a portion of the mutant protein must get to the cell membranes in the inner ear. From there, the team studied how the clarin1 mutant protein is transported to the membrane, so they can target that system therapeutically. To study this, the genetically engineered zebrafish models had their gene coding for zebrafish clarin1 replaced with human versions.

“Like mammals, zebrafish also develop sensory hair in the inner ear,” said Alagramam. “Also, considerable evidence indicates conservation of gene function in the hair cells of the inner ear across species, from zebrafish to humans.”

A portion of the fish were given normal human clarin1 while others were given the mutant clarin1. Using Zebrafish to study hearing offered several advantages for Alagramam and his team.

“Zebrafish larvae are transparent with accessible hair cells, which means we can see the hair cells in the inner ear under a microscope and perform experiments in the live organism,” Alagramam told The Hearing Journal. “This is not possible to do with mammals because the inner ear is deep in a chamber protected by thick and opaque temporal bone.”

With the transparent larvae, the team was able to find the unconventional cellular pathways that they were searching for. They tracked human clarin1 moving through the zebrafish hair cells by using fluorescent labels to track human clarin1. The mutant clarin1 gets to the cell membrane via proteins and trafficking mechanisms within the cell, normally used by misfolded proteins fixed in certain cellular compartments. The research noted that the mutant clarin1 was trapped within the tubules of the cells. Alagramam's team gathered that if this protein were to be freed, there may be a therapeutic benefit. They tested two drugs to target this issue. The first was thapsigargin, an anti-cancer drug, and artemisinin, an anti-malarial drug.

Both drugs liberated the trapped protein and allowed clarin1 levels to rise in the membrane. However, artemisinin was the more effective of the two. The drug even improved the hearing and balance in the treated fish, as compared to the untreated fish. In order for zebrafish to survive, they must be able to swim normally. This ability depends on their balance and capability to detect water movement, which are both related to hair cell function. Survival rates of the zebrafish with the mutant clari1 increased from five percent to 45 percent after being treated with artemisinin. Alagramam and his team also reported that artemisinin has the potential to alleviate vision loss that is also caused by clarin1 mutations. They will proceed to study the clarin1 mutation, but this time in combination with artemisinin. “[We want] to test the efficacy of the anti-malarial drug to mitigate hearing loss in a mouse model of USH3A,” said Alagramam. “If that is successful, we can move to clinical trials.”

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