Antibiotic can turn off transplanted genes in brain

A pair of genes transplanted into the brains of lab rats can lead to the production of a neurochemical that is in short supply in many people with Parkinson's disease.

But what happens if the irrevocable delivery of the genes goes bad and causes unwanted side effects?

That concern has been on the minds of researchers seeking ways to spur brain cells into producing the neurochemical, dopamine.

Scientists at the University of Florida say they may have an answer for transplanted genes that may have run amok.

In an article published in the online version of the journal Molecular Therapy, a team at UF's McKnight Brain Institute and Powell Gene Therapy Center report that a common antibiotic appears to be able to slow down or turn off the genes after they have been transplanted.

This could be significant, because the UF researchers think earlier experimental attempts using growth factors - naturally occurring substances that cause cells to grow and divide - to revive dying brain cells and get them to produce dopamine again may have failed because they occurred too late in the course of the disease.

Doctors would be reluctant to try the gene transplant technique for revitalizing dopamine production if it carried the risk of inflicting permanent negative side effects on people who are still relatively health because their Parkinson's disease is in early stages.

Ronald Mandel, a professor of neuroscience at UF, and his colleagues have been studying the use of a virus as a "vector" that delivers the genes needed to protect brain cells that produce dopamine.

"We have worked every day for 10 years to design a construct to the gene delivery vector that enhances the safety profile of gene transfer for Parkinson's disease," Mandel says.

In the technique the UF team has been exploring, the two transplanted genes must work together to produce the protein molecule that plays a key role in the process.

The researchers have now discovered that the antibiotic doxycycline, depending on the dose given, can slow down or turn off that protein production by the transplanted genes.

"With that added measure of safety, we believe we can intervene with gene transfer in patients at earlier stages of the disease," Mandel says.

Doxycycline, a member of the tetracycline class of antibiotics, is used to treat various forms of bacterial infection and acne.

If the UF researchers are right, this could be the first time scientists would be able to regulate a gene therapy after the treatment has been delivered.

"With this technique, you could adjust the therapy in the patient," said Fredric P. Manfredsson, a postdoctoral associate in UF's department of neuroscience. "That would be extremely helpful because no one is really certain yet what dosage is required for a protective effect in humans."

Being able to control gene regulation could help the development of safety gene therapies, according to Mark Tuszynski, a professor of neurosciences and director of the Center for Neural Repair at the University of California, San Diego.

"The work of Dr. Mandel and colleagues brings us an important step closer to this goal," says Tuszynski, who had no involvement in the UF research

For more information go to: www.parkinsonresearchfoundation.org