Aminoglycosides are cheap and effective antibiotics that can come with a heavy price—hearing loss. Commonly used in developing countries and for infants in neonatal intensive care, just a few days of treatment can cause these powerful drugs to build up in the inner ear and kill the sensory hair cells that enable hearing, resulting in irreversible damage.
Now, researchers have found a potential method to spare hair cells from these destructive antibiotics—and it comes from an Indian pepper plant. The alkaloid piplartine prevented hearing loss in zebrafish and mice treated with aminoglycosides, presenting a plant-based solution for a global health problem which, as of yet, has no approved treatment. The results appeared in Science Translational Medicine on Aug. 7.
“This is one of the most promising treatments for aminoglycoside-induced hearing loss under development in preclinical models,” Alan Cheng, M.D., an otolaryngologist at Stanford University who was not involved with the research, told Fierce Biotech in an email.
Small and stripy zebrafish are popular model organisms in the world of hearing research because the hair cells they use to hear are strikingly similar to ours. After using zebrafish for other projects, like studying the function of proteins made by hair cells, biomedical researcher Marisa Zallocchi, Ph.D., started using the aquatic animals to test chemicals that might protect against hearing loss. She focused on aminoglycoside-induced hearing loss because there are no current methods to treat it.
“I thought going in that direction will be interesting, because people will benefit from that,” Zallocchi, of Creighton University in Nebraska, told Fierce Biotech in an interview. Because they are inexpensive and don’t need to be refrigerated, aminoglycosides are used more in developing countries than they are in the U.S. Healthcare practitioners in these places often don’t have the ability to accommodate people who develop disabling hearing loss due to the drugs, Zallocchi notes.
Zallocchi started her search with a molecule called quinoxaline. Working with a chemist, she began screening hundreds of variants of the compound in zebrafish, one of which was piplartine, which can be found naturally in the Indian long pepper Piper longum. To her surprise, the pepper chemical proved the most potent. “I didn’t expect this one in particular to be better than the rest,” Zallocchi said, because of how different it is from the starting point, quinoxaline.
Once she saw that it worked in zebrafish, Zallocchi teamed up with Creighton graduate student Jonathan Fleegel to move the tests into mammals. They tweaked an existing mouse model so that when given the aminoglycoside kanamycin, the mice lost their hearing in a way that mirrored the hearing loss in human patients. They then gave some of the mice kanamycin alone, injected twice a day subcutaneously, and for others paired the kanamycin with piplartine injected into their abdomens once a day for 17 days, starting one day before kanamycin treatment began.
By monitoring brain stem activity in response to sounds, Zallocchi and colleagues saw that mice given the antibiotic alone began to lose their hearing, requiring louder and louder sounds to elicit a response. The mice given piplartine, however, were protected, and ended up losing significantly less of their hearing; at low frequencies, the piplartine totally preserved hearing, while at higher frequencies the losses were not as severe as those seen in mice given kanamycin alone.
By dissecting the inner ears of the mice and tracking the activity of enzymes and other proteins, the researchers found that piplartine may be protecting hair cells from damage by partially blocking a membrane channel protein called transient receptor vanilloid 1 (TRPV1). TRPV1 is a passageway that allows compounds to enter cells, and “it has been shown already that that channel is one of the main routes of entry of aminoglycosides,” Zallocchi said.
“The mechanisms by which piplartine confers protection are intriguing and should spark new lines of research in this area,” Cheng said. He believes it’s warranted to study piplartine’s safety and effectiveness in humans.
Zallocchi plans on launching a biotech company, in collaboration with Creighton University, to bring piplartine into the clinic. She plans to next test the piplartine-aminoglycoside combo in mice that have a bacterial infection like people receiving the treatment would—in the current study, the mice were healthy. She’s also looking into whether piplartine can protect against another source of hearing loss: loud noises.
Piplartine’s promise joins other recent advances biotechs have made in treating hearing loss. Regeneron reported two case studies earlier this year showing that its DB-OTO gene therapy, acquired from Decibel Therapeutics, restored hearing in two young children with mutations in the otoferlin gene that cause deafness. And after failing a phase 2 trial, Sensorion’s small molecule to preserve hearing after cochlear implantation began a comeback after a study found that it accumulated to meaningful levels in the inner ear.