A research team led by the University of California, Los Angeles (UCLA), has received a four-year, $2.7 million grant from the National Institutes of Health (NIH) to investigate how Zika virus damages the developing eye and identify potential treatments to protect infants from permanent vision impairment.
The project, led by Vaithi Arumugaswami, professor of molecular and medical pharmacology at UCLA's David Geffen School of Medicine, and Ashok Kumar, professor of ophthalmology, visual and anatomical sciences at Wayne State University School of Medicine, builds on previous research into the mechanisms of Zika-related retinal damage.
Although Zika virus is most widely associated with neurological birth defects, infection during pregnancy can also cause significant ocular abnormalities in infants, including damage to the retina and optic nerve. These complications, which form part of congenital Zika syndrome, can result in lifelong visual impairment.
Despite these risks, no vaccines or antiviral treatments are currently approved for Zika, and the biological mechanisms underlying its effects on ocular development remain poorly understood.
"Zika outbreaks are episodic, flaring up and then fading for years, which can make the threat easy to forget," said Arumugaswami, who is also a member of the UCLA Broad Stem Cell Research Center and California NanoSystems Institute, in a recent press release. "The time to study the virus is now, while things are quiet, not after an outbreak has taken hold and a lot of babies and families are suffering."
Previous NIH-funded research by the team examined how Zika virus infects retinal pigment epithelium (RPE) cells, which play an essential role in supporting the retina's photoreceptors.
Using a technique that separates cellular protein complexes according to size, the researchers identified interactions between viral proteins and host proteins involved in ocular development and cellular energy regulation.
When several of these host proteins were experimentally reduced, viral replication increased, suggesting they may provide a natural defense against infection.
The researchers also screened thousands of potential therapeutic compounds, identifying several candidates capable of inhibiting Zika infection. Initial experiments in infected adult mice indicated that some of these compounds could also reduce ocular damage.
The protein interaction studies were conducted in collaboration with Mehdi Bouhaddou, PhD, while drug screening was undertaken with Robert Damoiseaux, PhD, both of UCLA.
With the latest funding, the researchers will further investigate these molecular interactions using three complementary experimental models: laboratory-grown RPE cells, human stem cell-derived retinal organoids and newborn mice infected with Zika virus.
The retinal organoids, which replicate certain features of developing human retinal tissue, will allow researchers to examine how infection disrupts cellular development in a controlled laboratory setting.
Meanwhile, the newborn mouse model will provide insight into how Zika affects an eye that is still developing, as murine ocular development continues after birth.
Alongside investigating disease mechanisms, the team will evaluate whether previously identified antiviral compounds can prevent or reduce retinal damage in infected newborn mice.
The researchers will also assess whether these treatments interfere with normal retinal development, a critical consideration for therapies that could eventually be administered during pregnancy.
Early laboratory investigations have suggested that several of the candidate compounds may also inhibit other mosquito-borne viruses, including dengue and West Nile, raising the possibility of broader antiviral applications.
However, further preclinical research will be necessary to establish their safety, efficacy and suitability for eventual human trials.
The project comes amid continued concerns surrounding mosquito-borne infections, particularly as Aedes aegypti, the primary vector for Zika transmission, becomes established in parts of the United States.
Although there is currently no major global Zika outbreak, the researchers emphasize the importance of developing preventive strategies before future outbreaks occur.
"We need to get a drug that goes to clinical trial and benefits patients," said Arumugaswami. "That's the bottom line."
Source: UCLA Health.
