Killing the Common Cold Virus With a DNAzyme Cleaver

Ingrid Hein

February 25, 2019

The vast majority of cases of the common cold can be wiped out with catalytic DNA technology, according to new research from a German team.

"The idea of curing the common cold has been a Holy Grail of sorts in infectious disease," said Neil Romberg, MD, who is moderating sessions at the American Academy of Allergy, Asthma and Immunology 2019 Meeting in San Francisco, where this work is being presented.

Currently, there are about 150 known strains of rhinovirus. "They are all similar, but different enough that no single vaccine can protect against all of them," explained investigator Daniel Potaczek, MD, from Philipps University Marburg in Germany.

"We know that rhinovirus is responsible for the majority of exacerbations of asthma and COPD, but so far, there is no drug on the market that is specific for rhinovirus," Potaczek told Medscape Medical News. "In healthy people, rhinovirus just causes a cold, but in patients with asthma, it can lead to exacerbation of disease, leading to hospitalization," In fact, rhinovirus underlies about 60% of asthma exacerbations in adults and even more in children.

So Potaczek and his colleagues set out to design a DNAzyme that could effectively put rhinovirus genomic RNA in a headlock and chop it down the middle by targeting the 5′-untranslated (UTR) region, an area important to the integrity and function of rhinovirus RNA.

"By destroying the rhinovirus genomic RNA, we can effectively destroy the virus," Potaczek reported.

Chopping Rhinovirus RNA Down the Middle

"We realized that RNA is protected from both sides, but it's no longer protected if disrupted in the middle," said Potaczek. "If you somehow cut the middle, each fragment is susceptible to further cleavage by intracellular nucleases."

The team tested their method on three common rhinovirus strains (RVA1, RVA16, and RVA29) typically used by lab researchers.

They designed 226 candidate DNAzymes to target two regions of the rhinovirus that are similar in all strains: the 5′-UTR and the cis-acting replication element. They tested the specific catalytic activity of each candidate DNAzyme.

The team then performed bioinformatics analyses to test the candidate DNAzymes for coverage of 322 published rhinovirus genomic sequences. However, no single molecule was effective enough to cleave the rhinovirus RNA and cover multiple rhinovirus strains at once.

So the team modified the two 5′-UTR candidates that showed promise. With a longer binding domain, they were able to slice the rhinovirus RNA right down the middle, ultimately destroying the virus.

This is not the first time DNAzymes have had a day in the sun. A randomized, placebo-controlled phase 2 trial showed that the SB010 DNAzyme could cleave and inactivate GATA3 messenger RNA (N Engl J Med. 2015;372:1987-1995). After 28 days of treatment, both late and early asthmatic responses were attenuated in patients who received the DNAzyme. There was also significant attenuation of the Th2-regulated inflammatory response.

"DNAzymes are striking back," Potaczek said. "The enthusiasm for the antisense molecules had gone down, but it's going up again."

"There is a big need for treatment against rhinovirus, especially for patients with asthma," he added. "Treating these patients with an antiretroviral would lead to a substantial reduction in medical costs and improve quality of life."

Not only does the DNAzyme attack 98% of rhinovirus strains, it is probably resistant to escape mutations in rhinovirus genomic RNA. "The region targeted by our DNAzymes is so important" that any mutations would render the rhinovirus genomic RNA unable to function, he explained. And there was no toxicity in any of the cells tested.

Years Away From Treatment

"I think this could potentially be used to prevent the common cold," Potaczek said. Still, he predicted, it will likely take at least 8 years of preclinical and human clinical trials before a drug is ready to enter the market.

"It's an exciting finding, but very far away from implementation on a human," said Romberg, who id from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. The technology works in a test tube but has yet to be tested "in the lungs and respiratory tract of animals."

However, the research is important. Upper respiratory tract infection is a common reason people visit the doctor's office. "Patients are frustrated with the fact that we're unable to do anything other than recommend rest, soup, and TLC, so it would be a plus to have a drug, as long as there aren't any downsides," Romberg explained.

"This would be a life-saving intervention if we can get it to work in humans" because the common cold can be dangerous for some patients, he added.

Potaczek and Romberg have disclosed no relevant financial relationships.

American Academy of Allergy, Asthma and Immunology (AAAAI) 2019 Meeting: Abstract 299. Presented February 23, 2019.

Follow Medscape on Twitter @Medscape and Ingrid Hein @ingridhein


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