Drug study uncovers unintended side effects: 'GENE-SILENCING' MEDICATION IS UK OPHTHALMOLOGIST'S FOCUS

By Sarah Vos

Mar. 27, 2008 (McClatchy-Tribune Regional News delivered by Newstex) --
A new class of drugs that are supposed to turn off unwanted genes might have unexpected side effects, according to a new study by a University of Kentucky researcher that was published Wednesday in the journal Nature.

The findings raise "paradigm shifting" questions about drugs stemming from the Nobel Prize-winning discovery of gene silencing, which has fueled research on new potential treatments for ailments ranging from cancer to kidney disease.

The drugs studied by Dr. Jayakrishna Ambati are designed to stop the progression of diseases like macular degeneration, an age-related eye disease, by shutting off the gene that causes the disease.

But the drugs, known as short interfering RNAs or siRNAs, don't work as intended, according to Ambati. In the case of macular degeneration, the drugs don't just inhibit unwanted blood vessel growth in the eye -- they inhibit blood vessel growth in other parts of the body.

Blood vessel growth is needed for normal body operations, from reproduction to cardiovascular health. In tests done by Ambati's lab on mice, the drugs prevented skin wounds from healing as quickly as they should.

"You don't just want to stop blood vessel growth everywhere," said Ambati, a professor of ophthalmology at UK and the study's lead author.

The discovery is "paradigm shifting," said Dr. Charis Eng, chairwoman of the Genomic Medicine Institute at the Cleveland Clinic who works with siRNAs in cancer research. "Up until now, we all believed it's absolutely specific for gene X, so it prevents gene X from doceed headlong in injecting these drugs into people and not know how these things work," he said.

SiRNAs are supposed to mimic a process called RNA interference, which occurs naturally in cells, and allows the body to prevent the expression of specific genes.

The 1998 discovery of gene silencing caused great excitement among researchers and biomedical companies: If scientists could successfully turn off or turn down a gene, they could stop the progression, or even prevent, a whole range of diseases.

Ambati looked at two drugs designed to treat macular degeneration: bevasiranib and AGN211745, which is being developed by Allergan (NYSE:AGN) , a company based in Irvine, Calif. AGN211745 is in phase II clinical trials. The company did not respond to a request for comment Wednesday.

When RNA interference occurs naturally, the process happens inside the cell. Ambati's discovery is that the synthetic molecules don't work the same way.

SiRNAs can't get inside the cell because they are too large and have the wrong electrical charge, he said. Instead, they bind to a receptor on the outside of the cell.

This receptor doesn't distinguish between molecules designed to block blood vessel growth in the retina or ones designed to block blood vessel growth elsewhere, he said

"It generically blocks blood vessel growth, regardless of what your sequence is," Ambati said.

Humans have the same receptor on their cells, Ambati said.

Reach Sarah Vos at (859) 231-3309 or 1-800-950-6397, Ext. 3309.

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