Chemistry trick may herald transformational next-generation RNAi therapeutics aimed at cancer, viral infections

November 17, 2014, University of California - San Diego

Small pieces of synthetic RNA trigger a RNA interference (RNAi) response that holds great therapeutic potential to treat a number of diseases, especially cancer and pandemic viruses. The problem is delivery—it is extremely difficult to get RNAi drugs inside the cells in which they are needed. To overcome this hurdle, researchers at University of California, San Diego School of Medicine have developed a way to chemically disguise RNAi drugs so that they are able to enter cells. Once inside, cellular machinery converts these disguised drug precursors—called siRNNs—into active RNAi drugs. The technique will publish Nov. 17 in Nature Biotechnology.

"Many current approaches use nanoparticles to deliver RNAi drugs into ," said Steven F. Dowdy, PhD, professor in the Department of Cellular and Molecular Medicine and the study's principal investigator. "While nanotechnology protects the RNAi , from a molecular perspective nanoparticles are huge, some 5,000 times larger than the RNAi drug itself. Think of delivering a package into your house by having an 18-wheeler truck drive it through your living room wall—that's nanoparticles carrying standard RNAi drugs. Now think of a package being slipped through the mail slot—that's siRNNs."

The beauty of RNAi is that it selectively blocks production of target proteins in a cell, a finding that garnered a Nobel Prize in 2006. While this is a normal process that all cells use, researchers have taken advantage of RNAi to inhibit specific proteins that cause disease when overproduced or mutated, such as in cancer. First, researchers generate RNAi drugs with a sequence that corresponds to the gene blueprint for the disease protein and then delivers them into cells. Once inside the cell, the RNAi drug is loaded into an enzyme that specifically slices the messenger RNA encoding the in half. This way, no protein is produced.

As cancer and viral genes mutate, RNAi drugs can be easily evolved to target them. This allows RNAi therapy to keep pace with the genetics of the disease—something that no other type of therapy can do. Unfortunately, due to their size and negatively charged chemical groups (phosphates) on their backbone, RNAi drugs are repelled by the cellular membrane and cannot be delivered into cells without a special delivery agent.

It took Dowdy and his team, including Bryan Meade, PhD, Khirud Gogoi, PhD, and Alexander S. Hamil, eight years to find a way to mask RNAi's negative phosphates in such a way that gets them into cells, but is still capable of inducing an RNAi response once inside.

In the end, the team added a chemical tag called a phosphotriester group. The phosphotriester neutralizes and protects the RNA backbone—converting the ribonucleic acid (RNA) to ribonucleic neutral (RNN), and thus giving the name siRNN. The neutral (uncharged) nature of siRNNs allows them to pass into the cell much more efficiently. Once inside the cell, enzymes cleave off the neutral phosphotriester group to expose a charged RNAi drug that shuts down production of the target disease protein. siRNNs represent a transformational next-generation RNAi drug.

"siRNNs are precursor drugs, or prodrugs, with no activity. It's like having a tool still in the box, it won't work until you take it out," Dowdy said. "Only when the packaging—the phosphotriester groups—is removed inside the cells do you have an active tool or RNAi drug."

The findings held up in a mouse model, too. There, Dowdy's team found that siRNNs were significantly more effective at blocking target protein production than typical RNAi drugs—demonstrating that once siRNNs get inside a cell they can do a better job.

"There remains a lot of work ahead to get this into the clinics. But, in theory, the therapeutic potential of siRNNs is endless," Dowdy said. "Particularly for cancer, viral infections and genetic diseases."

The siRNN technology forms the basis for Solstice Biologics, a biotech company in La Jolla, Calif. that is now taking the technique to the next level. Dowdy is a co-founder of Solstice Biologics and serves as a Board Director.

Explore further: Mammals defend against viruses differently than invertebrates

More information: Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications, Nature Biotechnology, DOI: 10.1038/nbt.3078

Related Stories

Mammals defend against viruses differently than invertebrates

June 23, 2014

Biologists have long wondered if mammals share the elegant system used by insects, bacteria and other invertebrates to defend against viral infection. Two back-to-back studies in the journal Science last year said the answer ...

RNA interference for human therapy

September 20, 2012

Leading scientists in the field investigated the potential of RNA interference (RNAi) technology as a therapeutic intervention for down-regulating the expression of disease-associated genes. Project deliverables hold significant ...

Mammalian body cells lack ancient viral defense mechanism

October 15, 2013

A team led by Chris Sullivan, a professor of molecular biosciences at The University of Texas at Austin, has provided the first positive evidence that RNA interference (RNAi), a biological process in which small RNA molecules ...

RNAi shows promise in gene therapy, researcher says

February 19, 2007

Three years ago Mark Kay, MD, PhD, published the first results showing that a biological phenomenon called RNA interference could be an effective gene therapy technique. Since then he has used RNAi gene therapy to effectively ...

A molecular toolkit for gene silencing

December 13, 2013

The team of Johannes Zuber at the IMP in Vienna, Austria, managed to overcome remaining key limitations of RNA interference (RNAi) - a unique method to specifically shut off genes. By using an optimized design, the scientists ...

Recommended for you

Galactic center visualization delivers star power

March 21, 2019

Want to take a trip to the center of the Milky Way? Check out a new immersive, ultra-high-definition visualization. This 360-movie offers an unparalleled opportunity to look around the center of the galaxy, from the vantage ...

Ultra-sharp images make old stars look absolutely marvelous

March 21, 2019

Using high-resolution adaptive optics imaging from the Gemini Observatory, astronomers have uncovered one of the oldest star clusters in the Milky Way Galaxy. The remarkably sharp image looks back into the early history of ...

When more women make decisions, the environment wins

March 21, 2019

When more women are involved in group decisions about land management, the group conserves more—particularly when offered financial incentives to do so, according to a new University of Colorado Boulder study published ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.