Taking a page from the playbook of viruses Small interfering RNAs hold rich therapeutic potential as a way of silencing specific genes, yet they are extremely unstable in blood and inefficiently transported through the body, so it’s difficult to deliver them to the locations where they are required. Dr. Alyssa Hill is drawing inspiration from nature by engineering ‘smart’ viral RNA structures into delivery vehicles, which could open up new possibilities in treatment. A class of
short, double-stranded RNA molecules known as small interfering RNAs (siRNAs) hold rich therapeutic potential, and there is considerable interest in using them to treat a variety of conditions. These siRNAs co-opt the RNA interference (RNAi) pathway, which is a naturally-occurring mechanism of gene silencing in human cells. “Nobel Prizewinning research in the late 1990s showed that we can hijack the RNAi pathway with siRNAs and silence the expression of disease-causing genes. These might be cancer-promoting genes, or genes that encode for mutated proteins,” says Dr. Alyssa Hill. However, siRNAs are degraded rapidly by nucleases, which are defense enzymes in the blood. They also do not distribute widely through the body or passively enter cells, which makes it difficult to use siRNAs as drugs. Currently, only two siRNA therapies are approved for use in patients. “Even though they’re potent, getting siRNAs to the places where they’re needed – intact – is incredibly difficult,” explains Dr. Hill.
stable RNA structure produced by flaviviruses to accommodate an siRNA, focusing on a consensus motif used by the virus. “We’re using the viral RNA motif as a blueprint, changing the parts of it that we can while at the same time maintaining its overall fold,” continues Dr. Hill. “We’re also incorporating an aptamer, which is a device to drive uptake into specific cell types.” The goal is to develop an all-in-one platform that is stable in the blood, while also able to move itself into specific cells. Changes in the structure of an siRNA may lead to differences in the way it interacts with the RNAi machinery, however, which is an important consideration in the project. “Are we compromising the activity of the siRNA by trying to fuse it with another structure?” asks Dr. Hill. There are often tradeoffs between the stability of a molecule and its potency as a drug, an issue Dr. Hill is investigating. “We’ve looked at that by introducing unmodified siRNAs into cells grown in the lab and measuring their activity on a reporter gene,” she explains. “We also have introduced the engineered
We’re using the viral RNA motif as a blueprint, changing the parts of it that we can while at the same time maintaining its overall fold. ‘Smart’ RNA structures This issue is at the heart of Dr. Hill’s work as the Principal Investigator of a Swiss National Science Foundation (SNSF)-funded project in which the aim is to engineer ‘smart’ viral RNA structures for siRNA delivery. Over millennia, flaviviruses (e.g., Yellow fever virus, Zika virus) and other viruses have evolved RNA structures with clever ways of evading decay, which Dr. Hill and her project team now plan to use in siRNAs. “We aim to repurpose them, to export that stability into siRNAs,” she outlines. The aim here is to engineer a harmless but ultra-
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molecules into cells and monitored their activity on the same reporter gene.” Evidence suggests that the engineered molecules are just as potent as unmodified siRNAs, and now Dr. Hill is looking further ahead. Once the stability and potency of the molecules has been established, the next step is to assess whether they can be targeted to disease-related cell types. “We’re considering a cell model of prostate cancer, which is a prevalent disease that has unmet clinical needs,” says Dr. Hill. The project itself is only a year in duration, yet Dr. Hill hopes it could provide a
springboard for further research. “It’s a very ambitious idea, and of course we want it to progress. This is a challenging field, but it would be exciting if our approach proves effective and we can move the idea forward.” Engineering ‘smart’ viral RNA structures for stable and targeted siRNA delivery Project Funding
SNSF grant number 190865
Contact Details
Alyssa C. Hill, Ph.D. ETH Zürich Institute of Pharmaceutical Sciences Vladimir-Prelog-Weg 1-5/10 8093 Zürich, Switzerland T: +41 44 633 74 15 E: alyssa.hill@pharma.ethz.ch : @alyssa_hill Alyssa C. Hill, Ph.D.
Dr. Hill is a postdoctoral research associate in the Institute of Pharmaceutical Sciences at ETH Zürich. Her research has been supported by awards from the National Science Foundation (Alexandria, Virginia, U.S.), the Novartis Research Foundation (Basel, Switzerland), and the Swiss National Science Foundation (Bern, Switzerland).
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