Gene Silencing Therapies Could Have Harmful Side Effects, Research Suggests

Ambati, professor and vice chair of ophthalmology and visual sciences at the University of Kentucky College of Medicine, and his colleagues have made a critical discovery that challenges the view that siRNA's therapeutic effects are imparted solely through RNA interference.

Ambati, professor and vice chair of ophthalmology and visual sciences at the University of Kentucky College of Medicine, and his colleagues have made a critical discovery that challenges the view that siRNA's therapeutic effects are imparted solely through RNA interference.

Ambati and collaborators argue that siRNA functions generically rather than specifically, thus the new class of drugs being formulated may actually adversely affect blood vessel growth in a variety of organs.

"siRNAs are used in every area of biomedical research and are thought to be exquisitely specific in targeting a single gene," Ambati said. "My lab made the surprising discovery that siRNAs, including those in clinical trials, do not enter cells or trigger RNAi. Rather, we found that they generically, regardless of their sequence or target, bind a receptor known as TLR3 on cell surfaces and block blood vessel growth in the eye, skin and a variety of other organs."

Blocking blood vessel growth is beneficial in a variety of diseases. Prime examples include wet AMD, an eye disease hallmarked by the abnormal growth of blood vessels beneath the retina, as well as cancer. However, blocking blood vessel growth by administering siRNA intravenously could be detrimental if it impacts other organs, according to Ambati's study.
Ambati, however, quickly notes the Nobel Prize-winning discovery is still valid.

"RNA interference does, of course, exist," said Ambati, a University Research Professor and the Dr. E. Vernon Smith & Eloise C. Smith Endowed Chair in Macular Degeneration Research. "It is just that siRNA functions differently than commonly believed — not via RNA interference."

Ambati said the main implications of his research are two fold:
1.    for researchers to understand how siRNAs actually work
2.    for clinical trials of siRNA to be approached with great caution.
Ambati's lab also showed that people with a mutation in the TLR3 receptor would be resistant to the generic effects of siRNAs, thereby providing hope for personalized medicine in this population.

The next steps, Ambati said, are to better understand the generic mechanism of siRNA that inhibits blood vessel growth and to discover how to render it useful in creating treatments for the many conditions that would benefit from such effects. His lab also will work to refine siRNAs to potentially achieve their promise of precise gene targeting.

Adapted from materials provided by University of Kentucky.