PHILOMATH, Oregon – Custom-designed molecules for treating human disease are being manufactured in an unlikely place: the tiny, forest-products town of Philomath. Inside a low-slung industrial building nestled among grasses and alders on the slopes of Oregon’s Coast Range, a small biotech firm called Gene Tools LLC is tailoring molecules that may someday help patients recover from infections like flu or chronic conditions like muscular dystrophy.
Invented by former Oregon State University biochemist Jim Summerton and his colleague Dwight Weller, these specialized, synthetic molecules are commonly called “Morpholinos,” short for the technological tongue twister, “Morpholino antisense oligomers.” These microscopic molecules with the mega-moniker bind to sequences of RNA, a major component of all living cells. Summerton and his team tailor them to block generations of harmful proteins. On the flipside, the Morpholinos can spur production of beneficial proteins by correcting genetic errors.
“Morpholinos have revolutionary potential for treatment of a broad range of human diseases, including viral, bacterial, age-related and genetic diseases,” says Hong Moulton, a biomedical scientist at OSU who studies these manufactured molecules. “But they suffer from poor delivery across the cell membrane into cells. My long-term research interest has been in inventing and improving delivery of Morpholinos.”
The problem is size. Morpholinos may be microscopic, but as molecules go, they’re quite large. To do their job, they must easily enter human cells, a difficult maneuver for the plus-sized molecules. While working for Morpholino inventor Summerton at his first startup, AVI Biopharma, Moulton invented a technology to improve delivery of Morpholinos to the cells of mice either with muscular dystrophy or infected with various viruses. Mice treated with the technology, which uses cell-penetrating peptides, got better and survived longer.
But when the company moved its research operation to Seattle. Moulton chose to stay in Oregon, continuing her work in the OSU College of Veterinary Medicine. Her work spans the campus, from chemical and cell biology in the Vet Med labs to fish biology studies at OSU’s Sinnhuber Aquatic Research Laboratory across the Willamette River.
Red Fish, Blue Fish
One of Moulton’s allies in moving Morpholinos closer to the marketplace is a tiny fish with a talent for switching color. Specially engineered for her at the Mayo Clinic, the genetically altered zebrafish has genes coded for two fluorescent proteins: one blue, the other red. She designed a Morpholino that lets her manipulate the fishes’ colors to test her theories of improved delivery.
“If I am able to deliver the Morpholinos into the nucleus of the cells, every cell in that fish will turn off the blue gene and turn on the red gene,” she explains. “The fish will turn from blue to red when viewed under a fluorescent microscope. That allows me to assess how much material is getting to the cells.”
Too, she can see where the Morpholinos are most effective. “Is it going to the brain? Is it going to the muscles? I can look at distribution of these molecules.”
Fighting the Flu
Moulton’s lab is also investigating the Morpholino’s effect on the flu virus. As a co-investigator on a multi-million dollar grant from the National Institutes of Health, she is collaborating with several teams across the United States to identify the human genes that interact with influenza. By the end of the five-year project, she expects to have Morpholinos that will effectively inhibit infection by the virus.
Next step? “We want to develop this into a therapeutic product that goes to drug development,” Moulton says.
–Story by Lyn Smith-Gloria, OSU College of Veterinary Medicine