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Engineered stem cells show promise for delivering drugs to brain
One of the great challenges for treating Parkinson's diseases and other neurodegenerative disorders is getting medicine to the right place in the brain.
The brain is a complex organ with many different types of cells and structures, and it is fortified with a protective barrier erected by blood vessels and glial cells -- the brain's structural building blocks -- that effectively blocks the delivery of most drugs from the bloodstream.
But now researchers have found a new way to sneak drugs past the blood-brain barrier by engineering and implanting progenitor brain cells derived from stem cells to produce and deliver a critical growth factor that has already shown clinical promise for treating Parkinson's disease.
Clive Svendsen and his colleagues at University of Wisconsin-Madison have described experiments that demonstrate that engineered human brain progenitor cells, transplanted into the brains of rats and monkeys, can effectively integrate into the brain and deliver medicine where it is needed.
The Wisconsin team obtained and grew large numbers of progenitor cells from human fetal brain tissue. They then engineered the cells to produce a growth factor known as glial cell line-derived neurotrophic factor ( GDNF ).
In some small but promising clinical trials, GDNF showed a marked ability to provide relief from the debilitating symptoms of Parkinson's. But the drug, which is expensive and hard to obtain, had to be pumped directly into the brains of Parkinson's patients for it to work, as it is unable to cross the blood-brain barrier.
In an effort to develop a less invasive strategy to effectively deliver the drug to the brain, Svendsen's team implanted the GDNF secreting cells into the brains of rats and elderly primates. The cells migrated within critical areas of the brain and produced the growth factor in quantities sufficient for improving the survival and function of the defective cells at the root of Parkinson's.
This work shows that stem cells can be used as drug delivery vehicles in the brain," says Svendsen, at the UW-Madison Waisman Center.
The new Wisconsin study, whose lead author is Soshana Behrstock, depended on formative brain cells that were coaxed from blank-slate stem cells. The progenitor neural cells were genetically modified to secrete the growth factor when implanted in the striatum, a large cluster of cells in the brain that controls movement, balance and walking.
To work effectively, the cells in the striatum require dopamine, a chemical that is produced deep in the brain and that travels up nerve fibers to the striatum where it is used to keep critical cells functional.
Loss of the ability to produce dopamine is the root cause of Parkinson's, a disease that afflicts about 1.5 million people in the United States.
In the new Wisconsin study, the GDNF-producing cells transplanted in the striatum of animals with a condition like Parkinson's showed not only that a critical drug could be delivered to the right place, but that the drug was delivered in a way that promoted its therapeutic potential.
The researchers reported new nerve fiber growth in the striatum and the transport of the critical nerve growth factor GDNF from the striatum to the substantia niagra, the part of the brain that harbors the cells that produce dopamine.
" In Parkinson's, the striatum loses fibers," Svendsen explains. But cells in the striatum exposed to GDNF in the Wisconsin study showed an ability to recover and sprout new fibers.
" It actually seems to work better in the striatum," Svendsen says. " The bonus is it gets transported back to the substantia niagra."
The transplanted cells, according to Behrstock, survived and continued to produce GDNF in laboratory animals for up to three months.
One hurdle that needs to be overcome before such a technique could be attempted in human patients, says Svendsen, is developing a method to switch transplanted cells on or off and thus control their drug delivery capabilities. Working with engineered cells in culture, the Wisconsin group found they could switch the cells on and off using a second drug. Doing so in animal models, however, was more difficult and the issue will need to be addressed in new experiments, according to Svendsen.
The new study, Svendsen argues, proves that progenitor cells -- cells that can now be made in large quantities in the laboratory -- can be crafted to help clinicians deliver drugs where they are needed most in the body. Delivering medicine to the brain, whose blood-brain barrier effectively excludes more than 70 percent of all drugs, would be an especially valuable use for the cells. Such a new method may be useful for treating a number of neurodegenerative diseases beyond Parkinson's, he says.
