Engineered stem cells show promise for sneaking drugs into the brain

December 15, 2005

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 scientists 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.

Writing this week (Dec. 15, 2005) in the journal Gene Therapy, University of Wisconsin-Madison neuroscientist Clive Svendsen and his colleagues describe 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, a professor of anatomy whose laboratory is 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 terminal (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.

In addition to Svendsen and Behrstock, authors of the new Gene Therapy paper include Allison Ebert, Jacqueline McHugh, Stephen Vosberg, Elizabeth Capowski, Bernard Schneider and Derek Hei, all of UW-Madison; Jeffery Kordower of Rush University Medical Center; and Patrick Aebischer of the Swiss Federal Institute of Technology.
-end-
-- Terry Devitt, 608-262-8282, trdevitt@wisc.edu

University of Wisconsin-Madison

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.