In Hong Moulton’s lab at the Oregon State University Carlson College of Veterinary Medicine, researchers are creating delivery systems to get specially designed molecules called morpholinos directly into cells where they can block or alter the genetic expression associated with diseases.
Once researchers can unlock the right delivery method to get the molecules into targeted cells, this technology will have near-universal applications for disease treatment, from targeting the genetic mutations that cause Huntington’s disease to fighting infectious diseases like COVID-19.
Morpholinos work by attaching to RNA, the molecules that transfer genetic instructions inside cells. They can be chemically tailored to bind to any specific site on the RNA of a cell or virus, depending on the disease and which genes are involved. In binding to the RNA, they can turn specific genes on or off or block viruses from copying themselves.
Drugs that can bind to RNA and control genetic expression are fairly new in the pharmaceutical industry, although some FDA-approved morpholino drugs are already on the market. But those aren’t yet well-enabled for delivery, said Scott Bittner, postdoctoral scholar in Moulton’s lab.
“What we’re doing is the next generation of this type of universal therapeutics,” Bittner said. “We’re making it so you can get significant amounts of a drug into targeted tissue and get really specific effects. It’s sort of the front end of what’s going to become universal genetic medicine.”
To reach their intended RNA target, morpholinos must overcome two major obstacles, Moulton explained. First they need to attach to the cell membrane. Then once inside, they must escape tiny cellular compartments called endosomes. The OSU team is building delivery platforms designed to carry this therapeutic “warhead” into the cell’s cytoplasm and nucleus where it can find the RNA and bind onto it.
One of these delivery platforms has already been shown to be effective in treating SARS-CoV-2, the virus that causes COVID-19. In 2024, Moulton and Bittner were part of a team that developed a specific morpholino that successfully inhibited the growth of multiple SARS-CoV-2 variants. Unfortunately, the five-year project was terminated two years early last April when the current federal administration slashed research funding nationwide.
Part of what makes morpholino delivery effective is the stability of morpholinos once they get inside cells. Once they get past the cell membrane, they can stick around for a long time without degrading, enabling long-lasting therapeutic effects. This durability can reduce dose frequency and help lower treatment costs. Moulton said one of her previous studies found sustained activity up to 17 weeks after a four initial daily doses of treatment in animal tests.
Moulton’s lab is currently working on two grant projects:
For pharmaceutical company Eli Lilly, they are testing different antibody-based platforms as delivery vehicles to help the morpholinos get where they need to be.
For the U.S. Department of Defense, they are working on a delivery system that can reach the brain to treat the Powassan virus, a tickborne pathogen that causes neurological illness. The virus is often fatal and leaves survivors with long-term problems with cognition and movement. Due to climate change, the ticks that carry Powassan are expanding their territory and pool of potential victims. Currently, there is no antiviral treatment for Powassan.
The challenge for Moulton’s team is getting a morpholino directly into the brain, which means crossing the blood-brain barrier, the border that protects the brain from pathogens and other harmful molecules floating around in the circulatory system. It’s a lot trickier than delivering a morpholino into the respiratory system via nasal spray to target SARS-CoV-2. But Bittner has had positive early results showing brain activity with some of the compounds he’s been working on, which Moulton called “very encouraging.”
Moulton’s team is also collaborating with the University of Alberta on research into morpholino delivery for muscular dystrophies and spinal muscular atrophy, with the University of North Carolina-Chapel Hill on cystic fibrosis and with the National Institutes of Health and Icahn School of Medicine at Mount Sinai on the Nipah virus.
