Oregon Health & Science University researchers have figured out how to turn a mouse into a factory for human liver cells that can be used to test how pharmaceuticals are metabolized.
The technique, published in the journal Nature Biotechnology, could soon become the gold standard not only for examining drug metabolism in the liver, which helps scientists determine a drug's toxicity. But it also can be used as a platform for testing new therapies against infectious diseases that attack the liver, such as hepatitis C and malaria.
"This has the potential, if it becomes easy to use and widely available, to change the way drugs are tested," said study leader Markus Grompe, M.D., professor of molecular and medical genetics, and pediatrics, OHSU School of Medicine.
"In terms of fostering research, this will be great for malaria, this will be great for hepatitis, this will be great for liver stem cells, this will be great for gene therapy. It will allow a lot of what's going on only in rodents to be taken into a much more clinical setting. So I'm very happy about it."
Arundeep S. Pradhan, director of OHSU's Technology & Research Collaborations office, which is responsible for transferring the university's research discoveries to the commercial sector, said market demand for Grompe's discovery is high. OHSU has filed a patent application on the technology and, in cooperation with Grompe, has spun it off into a Portland-based start-up company named Yecuris through the university's Springboard Program.
"Yecuris is a viable start-up company based on significant developments at OHSU," Pradhan said. "The products developed by Yecuris have the potential to ease one of the bottlenecks in drug development: the testing of drugs for liver toxicity."
The worldwide market for human liver cells the pharmaceutical industry uses for testing candidate drug compounds is estimated at $2 billion a year, according to a business plan for Yecuris. That's because the liver is the principal site for the metabolism of drug compounds.
"Chemicals are converted to other chemicals in the liver, and you can't predict how the compound you developed in the lab will be converted," Grompe said. "Often, it's not the drug that's toxic, but the resulting metabolites. The conversion of drugs cannot be predicted with any current technology, such as computer models. You actually have to see what human liver cells do with any given drug."
And human liver cells must be used instead of cells from laboratory animals because liver enzymes that break down these compounds are species specific. "Animal liver cells process drugs quite differently than human liver cells do," he said.
Another obstacle for drug companies is the human liver cell market is filled with poor-quality or nonviable cells isolated primarily from human cadaver livers left over after high-quality livers needed for transplants are harvested. Plus, the cells are only available when specimens become available, which can be any hour of the day or night, and they must be used immediately.
"There are a number of companies that take these leftover livers, process them and ship the cells to people who need them for testing," Grompe said. "You have no control over when you get them, and you have no control over the quality when you get them. Many batches of cells are bad, low quality." And human liver cells from living sources are difficult to expand in laboratory tissue cultures.