Strong immune response to new siRNA drugs in development may cause toxic side effects

May 20, 2009

Small synthetic fragments of genetic material called small interfering RNA (siRNA) can block production of abnormal proteins; however, these exciting new drug candidates can also induce a strong immune response, causing toxic side effects. Understanding how siRNA stimulates this undesirable immune activity, how to test for it, and how to design siRNA drugs to avoid it are critical topics explored in a timely review article published online ahead of print in Oligonucleotides, a peer-reviewed journal published by Mary Ann Liebert.

siRNAs are duplex structures comprised of short oligonucleotide sequences. The discovery that naturally occurring and synthetic siRNAs can effectively prevent expression of a gene sparked intense interest in developing siRNAs as drugs. However, depending on the structure and sequence of a siRNA and how it is delivered, it may induce a potent innate immune response in humans, stimulating the release of inflammatory chemicals such as cytokines and interferons.

Exploring the possibility of designing synthetic siRNAs and developing novel delivery methods that would exploit the drug-like capabilities of siRNA while preventing toxic side effects, researchers are working to understand the mechanism by which siRNA stimulates the immune system. In the article entitled, "siRNA and Innate Immunity," Marjorie Robbins, Adam Judge, and Ian MacLachlan, from Tekmira Pharmaceuticals (Burnaby, British Columbia, Canada), describe the different possible mechanisms for siRNA-mediated immune activation in various cell types, present preferable siRNA sequences and strategies for chemically modifying the siRNA to minimize its immunostimulatory effects, and suggest experimental methods for studying the safety of siRNA therapeutics.

The authors conclude, "We are confident that through the judicious application of well-informed siRNA design and the use of increasingly effective delivery systems, demonstrations of systemic siRNA in human subjects will soon be realized."

"This is perhaps the most comprehensive review on siRNAs and innate immunity to date and a must read for anyone using siRNAs therapeutically," says John Rossi, PhD, Co-Editor-in-Chief of Oligonucleotides and Professor in the Department of Molecular Biology, Beckman Research Institute of the City of Hope (Duarte, CA).

More information: The article is available free online at www.liebertpub.com/oli

Source: Mary Ann Liebert, Inc.

Explore further: Scientists discover new clues to how weight loss is regulated

add to favorites email to friend print save as pdf

Related Stories

Pack 'Em In -- Gold Nanoparticles Improve Gene Regulation

Feb 23, 2009

Investigators at Northwestern University have found that packing small interfering RNA (siRNA) molecules onto the surface of a gold nanoparticle can protect siRNAs from degradation and increase their ability to regulate genes ...

Physician revolutionizes gene research

Mar 26, 2008

A dramatic new study published in the most recent issue of Nature questions some of the mechanisms underlying a new class of drugs based on Nobel Prize-winning work designed to fight diseases ranging from macular degeneration to dia ...

Team demos safety of RNA therapy

Sep 26, 2007

Researchers from MIT, Alnylam Pharmaceuticals and other institutions have demonstrated the safety of a promising type of genetic therapy that could lead to treatments for a wide range of diseases such as cancer.

Recommended for you

Testing time for stem cells

24 minutes ago

DefiniGEN is one of the first commercial opportunities to arise from Cambridge's expertise in stem cell research. Here, we look at some of the fundamental research that enables it to supply liver and pancreatic ...

Team finds key signaling pathway in cause of preeclampsia

19 hours ago

A team of researchers led by a Wayne State University School of Medicine associate professor of obstetrics and gynecology has published findings that provide novel insight into the cause of preeclampsia, the leading cause ...

Rapid test to diagnose severe sepsis

23 hours ago

A new test, developed by University of British Columbia researchers, could help physicians predict within an hour if a patient will develop severe sepsis so they can begin treatment immediately.

User comments : 0