Researchers from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have received a $3.5 million grant from the National Institutes of Health to develop treatments for mpox, targeting a newly emergent strain that has shown increased virulence and transmission capabilities.
The five-year grant was awarded to principal investigator Dr. Vaithilingaraja Arumugaswami, professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, along with collaborator Robert Damoiseaux, director of UCLA's Molecular Screening Shared Resource, and co-principal investigator Ashok Kumar, professor of ophthalmology at Wayne State University School of Medicine.
Evolving Viral Threat Demands New Therapeutic Approaches
Mpox, caused by infection with mpox virus formerly known as monkeypox virus, produces flu-like symptoms and lesions that can spread across the body and sometimes infect the eyes. While the 2022 outbreak led to more than 100,000 cases worldwide, including over 32,000 in the U.S., new outbreaks surged in 2024, particularly in the Democratic Republic of Congo and surrounding countries where a newer, more virulent strain has led to increased deaths, especially among children.
The virus has rapidly evolved over the past three years into different strains that can spread more easily between humans. While much of the 2022 outbreak involved sexual transmission and intimate contact, the strain spreading most widely now can transmit through close personal contact of many kinds, including sharing linens or caring for sick children. Children are particularly vulnerable to this strain.
Breakthrough Drug Discovery Targets Immune Evasion
The UCLA-led team has already identified several promising drug candidates through screening thousands of compounds. What makes these discoveries particularly significant is their mechanism of action, which addresses how newer mpox strains evade the immune system.
Unlike most DNA viruses that replicate inside the nucleus of human cells, mpox virus replicates in the cytoplasm, outside the nucleus. Human cells are designed to recognize foreign DNA in the cytoplasm as a danger signal, using a pathway known as cGAS-STING to trigger an immune response. However, newer strains of mpox have evolved to shut down this STING protein more efficiently, allowing the virus to evade immune detection.
"One of our lead drug candidates turns STING back on — essentially restoring the cell's natural defense response," explained the research team. In mouse models of mpox infection, this drug candidate efficiently blocked viral replication without any toxicity.
Advancing to Human Tissue Models
The NIH grant will enable the team to advance these promising findings from mouse studies into human tissue models. The researchers are collaborating with Dr. Kumar, who is using limbal stem cells from donated human corneas to grow eye tissue in the lab and contributing to the development of an ocular mpox mouse model.
The team is also testing the drug in stem cell-derived human skin organoids — miniature lab-grown skin tissues that mimic the structure and function of real human skin. These models will allow researchers to study how the virus infects different cell types and test whether their drug can stop infection from spreading in sensitive areas like the eye.
If these studies prove successful, the researchers hope to approach the FDA next year to begin discussions about IND-enabling (investigational new drug) preclinical studies essential for human clinical trials.
Three-Pronged Research Strategy
The UCLA-led team will work toward three specific goals with the new funding:
Understanding how mpox virus spreads and causes injury within skin and eye tissue through studies using human stem cell-based models, identifying the genetic mutations that are making newer strains of mpox virus more infectious and lethal, and developing new classes of antiviral drugs to treat mpox infection and stop viral transmission.
Strategic Importance Beyond Current U.S. Cases
While only a handful of cases from the newer strain have been reported in the U.S. so far, primarily in travelers, experts emphasize that the virus is rapidly evolving in ways that could eventually make it far more dangerous and widespread.
"Viruses don't stop evolving just because we stop paying attention," the research team noted. "The longer it continues circulating anywhere in the world, the more likely it is to gain new mutations that make it even more contagious or dangerous — including here in the U.S."
Antiviral drugs provide an essential tool, especially for people who are already infected. Small-molecule drugs are often faster and cheaper to manufacture and distribute than vaccines and can help infected people clear the virus and prevent them from spreading it to others, limiting the virus's ability to evolve further.
The research addresses a critical gap in mpox treatment options. While there are two vaccines against smallpox that provide cross-protection against mpox, there isn't widespread access to vaccines in the countries hardest hit by current outbreaks, making antiviral drugs a crucial complementary approach to controlling transmission and preventing further viral evolution.
