Scientists Turns Mouse Into Factory For Human Liver Cells
Science Daily — 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.
In the last decade, scientists have studied whether mice could be
genetically engineered and bred to grow human liver cells. Early
results since 2004 showed it could be done, but the mice were
difficult to breed, the time window for transplanting human liver
cells into the mice was narrow, and the mouse liver, despite efforts
to make the animal immunodeficient, often rejected the human cells.
Grompe's laboratory now has a system in which those disadvantages
have been engineered out. It has created a severely immunodeficient
mouse strain that develops liver disease only when the animals don't
receive a protective drug called NTBC, allowing liver disease to be
turned on and off.
"Our mice on this medicine are perfectly healthy, normal mice, and
only when we take them off the NTBC do they get liver disease,"
Grompe said. "It's an easy system that any research lab should be
able to set up, which is very different from what's around now."
In fact, the human liver cells from the repopulated mouse livers are
indistinguishable from normal human liver cells, according to the
study. "The healthy human liver cells take over and replace the sick
mouse liver cells," Grompe said. "You end up with a healthy mouse
that makes human blood clotting factors, all the proteins the liver
makes, human bile, everything."
The mice also retain their unique traits for multiple generations,
and each mouse can be implanted with human liver cells at least four
times. Grompe estimates that each round of implantation can generate
more than 20 million viable human liver cells.
"We think we will have a real edge in terms of quality and
availability of cells," Grompe said. "We have a product. All we need
to do is scale up and start selling it to anyone who wants to buy
it."
In the coming months, Grompe's lab will develop a library of human
liver cells from common variations of human drug
metabolism. "Different humans metabolize drugs differently. So we
want to create a library of cells from different humans to capture
some of that variability,
Note: This story has been adapted from a news release issued by
Oregon Health & Science University.
http://www.scienced
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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