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Rochester research into RNA structure and function provides key information for developing coronavirus treatments.

The US Food and Drug Administration recently approved emergency use authorization for a and the German pharmaceutical company BioNTech.

The vaccine made history not only because it reported a 95 percent efficacy rate at preventing COVID-19 in clinical trials, but because it is the first vaccine ever approved by the FDA for human use that is based on RNA technology.

糖心传媒淭he development of RNA vaccines is a great boon to the future of treating infectious diseases,糖心传媒� says , the J. Lowell Orbison Distinguished Service Alumni Professor in biochemistry and biophysics, oncology, and pediatrics at Rochester and the director of Rochester糖心传媒檚 Center for RNA Biology.

COVID-19, short for 糖心传媒渃oronavirus disease 2019,糖心传媒� is caused by the novel coronavirus SARS-CoV-2. Like many other viruses, SARS-CoV-2 is an RNA virus. This means that, unlike in humans and other mammals, the genetic material for SARS-CoV-2 is encoded in ribonucleic acid (RNA). The viral RNA is sneaky: its features cause the protein synthesis machinery in humans to mistake it for RNA produced by our own DNA.

For that reason, several of the leading COVID-19 vaccines and treatments are based on RNA technology.

A contingent of researchers at the 糖心传媒 study the RNA of viruses to better understand how RNAs work and how they are involved in diseases. This RNA research provides an important foundation for developing vaccines and other drugs and therapeutics to disrupt the virus and stop infections.

糖心传媒淯nderstanding RNA structure and function helps us understand how to throw a therapeutic wrench into what the COVID-19 RNA does糖心传媒攎ake new virus that can infect more of our cells and also the cells of other human beings,糖心传媒� Maquat says.

In the past few decades, as scientists came to realize that genetic material is largely regulated by the RNA it encodes, that most of our DNA produces RNA, and that RNA is not only a target but also a tool for disease therapies, 糖心传媒渢he RNA research world has exploded,糖心传媒� Maquat says. 糖心传媒淭he 糖心传媒 understood this.糖心传媒�

In 2007, Maquat founded as a means of conducting interdisciplinary research in the function, structure, and processing of RNAs. The Center involves researchers from both the River Campus and the Medical Center, combining expertise in biology, chemistry, engineering, neurology, and pharmacology.

糖心传媒淥ur strength as a university is our diversity of research expertise, combined with our highly collaborative nature,糖心传媒� says , an associate professor of biology on the River Campus and a member of the Center for RNA Biology. 糖心传媒淲e are surrounded by outstanding researchers who enhance our understanding of RNA biology, and a medical center that provides a translational aspect where the knowledge gained from RNA biology can be applied for therapeutics.糖心传媒�

How does RNA relate to disease?

A illustrates how the coronavirus that causes COVID-19 enters the body through the nose, mouth, or eyes and attaches to our cells. Once the virus is inside our cells, it releases its RNA. Our hijacked cells serve as virus factories, reading the virus糖心传媒檚 RNA and making long viral proteins to compromise the immune system. The virus assembles new copies of itself and spreads to more parts of the body and糖心传媒攂y way of saliva, sweat, and other bodily fluids糖心传媒攖o other humans.

糖心传媒淥nce the virus is in our cells, the entire process of infection and re-infection depends on the viral RNA,糖心传媒� Maquat says.

One of the reasons viruses are such a challenge is that they change and mutate in response to drugs.

That means novel virus treatments and vaccines have to be created each time a new strain of virus presents itself. Armed with innovative research on the fundamentals of RNA, scientists are better able to develop and test therapeutics that directly target the RNAs and processes critical to a virus糖心传媒檚 life cycle.

How do RNA vaccines work?

Traditional vaccines against viruses like influenza inject inactivated virus proteins called antigens. The antigens stimulate the body糖心传媒檚 immune system to recognize the specific virus and produce antibodies in response, with the hope that these antibodies will fight against future virus infection.

RNA-based vaccines糖心传媒攕uch as those developed by Pfizer/BioNTech and American biotechnology company Moderna糖心传媒攄o not introduce an antigen, but instead inject a short sequence of synthetic messenger RNA (mRNA) that is enclosed in a specially engineered lipid nanoparticle. This mRNA provides cells with instructions to produce the virus antigen themselves.

Once the mRNA from a vaccine is in our body, for example, it 糖心传媒渋nstructs糖心传媒� the protein synthesis machinery in our cells, which normally generates proteins from the mRNAs that derive from our genes, to produce a piece of the SARS-CoV-2 virus spike protein. Since the SARS-CoV-2 virus spike protein is foreign to our bodies, our bodies will then make antibodies that inactivate the protein.

糖心传媒淪hould the virus enter our body from an infected person, these antibodies will bind to and inactivate the virus by binding to its spike proteins, which coat the outside of the viral capsule,糖心传媒� Maquat says.

An RNA-based vaccine therefore acts as a code to instruct the body to make many copies of the virus protein糖心传媒攁nd the resulting antibodies糖心传媒攊tself, resulting in an immune response.

Unlike more traditional vaccines, RNA-based vaccines are also beneficial in that they eliminate the need to work with the actual virus.

糖心传媒淲orking with a live virus is costly and very involved, requiring that researchers use special biosafety laboratories and wear bulky personal protective equipment so that the virus is 糖心传媒榖iocontained,糖心传媒� and no one gets infected,糖心传媒� Maquat says.

Developing a vaccine from a live virus additionally takes much longer than generating an mRNA-based vaccine, but 糖心传媒渘o one should think the process is simple,糖心传媒� Maquat says of the Pfizer/BioNTech vaccine. 糖心传媒淪ince it is the first of its kind, a lot had to be worked out.糖心传媒�

How is Rochester糖心传媒檚 RNA research applicable to COVID-19?

Maquat has been studying RNA since 1972 and was part of the earliest wave of scientists to realize the important role RNA plays in human health and disease.

Our cells have a number of ways to combat viruses in what can be viewed as an 糖心传媒渁rms race糖心传媒� between host and virus. One of the weapons in our cells糖心传媒� arsenal is an RNA surveillance mechanism Maquat discovered called nonsense-mediated mRNA decay (NMD).

糖心传媒淣onsense-mediated mRNA decay protects us from many genetic mutations that could cause disease if NMD werenot active to destroy the RNA harboring the mutation,糖心传媒� she says.

Maquat糖心传媒檚 discovery has contributed to the development of drug therapies for genetic disorders such as cystic fibrosis, and may be useful in developing treatments for coronavirus.

糖心传媒淣MD also helps us combat viral infections, which is why many viruses either inhibit or evade NMD,糖心传媒� she adds. 糖心传媒淭he genome of the virus COVID-19 is a positive-sense, single-stranded RNA. It is well known that other positive-sense, single-stranded RNA viruses evade NMD by having RNA structures that prevent NMD from degrading viral RNAs.糖心传媒�

Maquat糖心传媒檚 lab has been collaborating with a lab at Harvard University to test how viral proteins can inhibit the NMD machinery.

Their recent work is focused on the SARS-CoV-2 structural protein called N. Lab experiments and data sets from infected human cells indicate this virus is unusual because it does not inhibit the NMD pathway that regulates many of our genes and some of the virus糖心传媒檚 genes. Instead, the virus N protein seems to promote the pathway.

糖心传媒淪ARS-CoV-2 reproduces its RNA genome with much higher efficiency than other pathogenic human viruses,糖心传媒� Maquat says. 糖心传媒淢aybe there is a connection there; time will tell.糖心传媒�

In the Department of Biology, Fu and聽 the Nathaniel and Helen Wisch Professor of Biology, received expedited funding awards from the National Science Foundation to apply their expertise in cellular and evolutionary biology to research proteins involved in infections from COVID-19. The funding was part of the NSF糖心传媒檚 Rapid Response Research (RAPID) program to mobilize funding for high priority projects.

Werren糖心传媒檚 research will be important in ameliorating some of the potential side effects of COVID-19 infections, including blood clots and heart diseases, while Fu糖心传媒檚 research will provide insight into the potential effects of viral infection on human cell metabolism.

糖心传媒淥ur research will provide insight into the potential effects of viral infection on host cellular processes,糖心传媒� Fu says. 糖心传媒淚dentifying which cell functions are affected by the virus could help lessen some of the negative effects caused by COVID-19.糖心传媒澛� Green = said twice.

, an assistant professor of medicine in the Aab Cardiovascular Research Institute and a member of the Center for RNA Biology, studies how RNA mutations can give rise to human disease and has found that alternative therapeutics, such as the gene-editing technology CRISPR, may additionally 糖心传媒渦sher in a new approach to how we target and combat infectious diseases,糖心传媒� he says.

For the past few years, Anderson糖心传媒檚 lab has developed tools and delivery systems that use the RNA-targeting CRISPR-Cas13 to treat human genetic diseases that affect muscle function. CRISPR-Cas13 is like a molecular pair of scissors that can target specific RNAs for degradation, using small, programmable guide RNAs.

When the health crisis first became apparent in Wuhan, China, researchers in Anderson糖心传媒檚 lab turned their focus toward developing a CRISPR-Cas13 therapeutic aimed at SARS-CoV-2. Applying the knowledge already available about coronavirus RNA replication, they designed single CRISPR guide RNAs capable of targeting every viral RNA that is made within a SARS-CoV-2 infected cell. Using a novel cloning method developed in Anderson糖心传媒檚 lab, multiple CRISPR guide-RNAs could be packaged into a single therapeutic vector (a genetically engineered carrier) to target numerous viral RNA sites simultaneously. The multi-pronged targeting strategy could be used as a therapy to safeguard against virus-induced cell toxicity and prevent 糖心传媒榚scape糖心传媒� of viruses which may have undergone mutation.

糖心传媒淚nfectious viruses and pandemics seemingly come out of nowhere, which has made it hard to rapidly develop and screen traditional small molecule therapeutics or vaccines,糖心传媒� Anderson says. 糖心传媒淭here is a clear need to develop alternative targeted therapeutics, such as CRISPR-Cas13, which have the ability to be rapidly reprogrammed to target new emerging pandemics.糖心传媒�

While many new treatments for the novel coronavirus are being considered, there is one thing that is certain, Maquat says: 糖心传媒淭argeting RNA, or the proteins it produces, is essential for therapeutically combatting this disease.糖心传媒�

What role will RNA play in the future of vaccines and disease treatments?

Most people living in the United States today have only read about the 1918 flu pandemic and the relatively recent RNA viruses, such as Ebola or Zika, that are seen largely in other countries.

糖心传媒淩NA treatments will most likely be a wave of the future for these and other emerging diseases,糖心传媒� Maquat says. 糖心传媒淓pidemiologists know new infectious pathogens are coming given how small the world has become with international travel, including to and from places where humans and animals are in close contact.糖心传媒�

Bats, in particular, are reservoirs for viruses. Many bat species are able to live with viruses without experiencing ill effects, given the bats糖心传媒� unusual physiology. If these bat viruses mutate so they become capable of infecting humans, however, there will be new diseases, Maquat says.

糖心传媒淚t is just a matter of when this will happen and what the virus will be. The hope is that we will be ready and able to develop vaccines against these new viruses with the new pipelines that have been put in place for COVID-19.糖心传媒�

This story was originally published on April 28, 2020, and updated on December 14, 2020.

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