StemCell Therapy

As the new coronavirus makes its way around the world, doctors and researchers are searching for drugs to treat the ill and stop the spread of the disease, which has already killed more than 3,800 people since its introduction in Wuhan, China, in December.

The culprit virus is in the same family as the coronavirusesthat caused two other outbreaks, severe acute respiratory syndrome and MiddleEast respiratory syndrome. But the new coronavirus may be more infectious. Inearly March, the number of confirmed cases of the new disease, called COVID-19,had exceeded 100,000, far surpassing the more than 10,600 combined total casesof SARS and MERS.

Health officials are mainly relying on quarantines to try tocontain the virus spread. Such low-tech public health measures were effectiveat stopping SARS in 2004, Anthony Fauci, director of the U.S. NationalInstitute of Allergy and Infectious Diseases, said January 29 in Arlington,Va., at the annual American Society for Microbiologys Biothreats meeting.

But stopping the new virus may require a more aggressive approach. In China alone, about 300 clinical trials are in the works to treat sick patients with standard antiviral therapies, such as interferons, as well as stem cells, traditional Chinese medicines including acupuncture, and blood plasma from people who have already recovered from the virus.

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Researchers are not stopping there. They also are working to develop drugs to treat infections and vaccines to prevent them (SN: 3/14/20, p. 6). But creating therapies against new diseases often takes years, if not decades. With this new coronavirus, now known as SARS-CoV-2, nobody wants to wait that long. Thanks to their experience developing treatments against the MERS coronavirus, as well as other diseases, such as HIV, hepatitis C, influenza, Ebola and malaria, researchers are moving quickly to see what they can borrow to help patients sooner.

Finding new uses for old drugs is a good strategy,especially when racing to fight a fast-moving disease for which there is notreatment, says Karla Satchell, a microbiologist and immunologist atNorthwestern University Feinberg School of Medicine in Chicago.

Repurposing drugs is absolutely the best thing that could happen right now, Satchell says. Potentially, drugs that combat HIV or hepatitis C might be able to put the new coronavirus in check, too. Those drugs exist. Theyve been produced. Theyve been tested in patients, she says. Although these drugs arent approved to treat the new coronavirus disease, theyre a great place to start. One of the most promising candidates, however, hasnt yet been approved for any disease.

Scientists have been quick to reveal the new coronavirussecrets. When SARS emerged in 2002, researchers took about five months to get acomplete picture of the viruss genetic makeup, or genome. With the new virus,Chinese health officials first reported a cluster of mysterious pneumonia casesin Wuhan to the World Health Organization on December 31. By January 10, thenew coronaviruss full genome was made available to researchers worldwide inpublic databases.

A viruss genome is one of the most valuable toolsscientists have for understanding where the pathogen came from, how it worksand how to fight it. The first thing that coronaviruses have in common is thattheir genetic material is RNA, a chemical cousin to DNA.

Researchers immediately began comparing the newcoronaviruss genome with SARS and MERS viruses and other RNA viruses todetermine whether drugs developed to combat those disease-causing organismswould work against the new threat. As a result, some potential Achilles heelsof SARS-CoV-2 have already come to light.

One target is the viruss main protein-cutting enzyme,called M protease. RNA viruses often make one long string of proteins thatlater get cut into individual proteins to form various parts of the virus. Inthe new coronavirus, the M protease is one of 16 proteins that are linked likebeads on a string, says Stephen Burley, an oncologist and structural biologistat Rutgers University in Piscataway, N.J.

The virus can mature and infect new cells only if M proteasecan snip the string of proteins free, he says. Stop the protease from cuttingand the virus cant reproduce, or replicate.

Existing drugs might be able to stop the viruss M protease, two research groups proposed online January 29 at bioRxiv.org. One group suggested four drugs, including one used to treat hepatitis C and two aimed at HIV. A second group named 10candidates, including an anti-nausea medication, an antifungal drug and some cancer-fighting drugs.

HIV and hepatitis C are both RNA viruses that need aprotease to cut proteins free from long chains. Drugs that inhibit thoseproteases can reduce levels of the HIV and hepatitis C viruses to undetectable.Some of those drugs are now being tested against the new coronavirus inclinical trials in China.

The HIV drug Kaletra, also called Aluvia, is a combination of two protease inhibitors, lopinavir and ritonavir. Kaletras maker, the global pharmaceutical company AbbVie, announced on January 26 that it is donating the drug to be tested in COVID-19 patients in China. Kaletra will be tested alone or in combination with other drugs. For instance, researchers may combine Kaletra with Arbidol, a drug that prevents some viruses from fusing with and infecting human cells. Arbidol may be tested on its own as well.

But the HIV drugs may not work against the new virus because of two differences in the proteases. The coronavirus protease cuts proteins in different spots than the HIV protease does, say Guangdi Li of the Xiangya School of Public Health of Central South University in Changsha, China, and Erik De Clercq, a pioneer in HIV therapy at KU Leuven in Belgium. Secondly, the HIV drugs were designed to fit a pocket in HIVs protease that doesnt exist in the new coronaviruss protease, the researchers reported February 10 in Nature Reviews Drug Discovery.

Yet a few anecdotal accounts suggest the HIV drugs may help people with COVID-19 recover. Doctors at Rajavithi Hospital in Bangkok reported in a news briefing February 2 that they had treated a severely ill 70-year-old woman with high doses of a combination of lopinavir and ritonavir and the anti-influenza drug oseltamivir, which is sold as Tamiflu. Within 48 hours of treatment, the woman tested negative for the virus.

Her recovery may be due more to the HIV drugs than to oseltamivir. In 124 patients treated with oseltamivir at Zhongnan Hospital of Wuhan University, no effective outcomes were observed, doctors reported on February 7 in JAMA. Clinical trials in which these drugs are given to more people in carefully controlled conditions are needed to determine what to make of those isolated reports.

Researchers may be able to exploit a second weakness in thevirus: its copying process, specifically the enzymes known as RNA-dependent RNApolymerases that the virus uses to make copies of its RNA. Those enzymes areabsolutely essential, says Mark Denison, an evolutionary biologist atVanderbilt University School of Medicine in Nashville. If the enzyme doesntwork, you cant make new virus.

Denison and colleagues have been testing molecules that muckwith the copying machinery of RNA viruses. The molecules mimic the nucleotidesthat RNA polymerases string together to make viral genomes. Researchers havetested chemically altered versions of two RNA nucleotides adenosine andcytidine against a wide variety of RNA viruses in test tubes and in animals.The molecules get incorporated into the viral RNA and either stop it fromgrowing or they damage it by introducing mutations, Denison says.

One of the molecules that researchers are most excited aboutis an experimental drug called remdesivir. The drug is being tested in peoplewith COVID-19 because it can stop the MERS virus in the lab and in animalstudies. The drug has also been used in patients with Ebola, another RNA virus.

Remdesivir has been given to hundreds of people infected with Ebola, without causing serious side effects, but the drug hasnt been as effective as scientists had hoped, virologist Timothy Sheahan of the University of North Carolina at Chapel Hill said January 29 at the Biothreats meeting. In a clinical trial in Congo, for example, about 53 percent of Ebola patients treated with remdesivir died, researchers reported November 27 in the New England Journal of Medicine. Thats better than the 66 percent of infected people killed in the ongoing Ebola outbreak, but other drugs in the trial were more effective.

Several tests of remdesivir in lab animals infected with MERS have researchers still hopeful when it comes to the new coronavirus. In studies in both rhesus macaques and mice, remdesivir protected animals from lung damage whether the drug was given before or after infection. Molecular pathologist Emmie de Wit of NIAIDs Laboratory of Virology in Hamilton, Mont., and colleagues reported the monkey results February 13 in the Proceedings of the National Academy of Sciences.

Remdesivir appears to be one of the most promisingantiviral treatments tested in a nonhuman primate model to date, the teamwrote. The results also suggest remdesivir given before infection might helpprotect health care workers and family members of infected people from gettingsevere forms of the disease, Sheahan says.

Denison, Sheahan and colleagues tested remdesivir on infected human lung cells in the lab and in mice infected with MERS. Remdesivir was more potent at stopping the MERS virus than HIV drugs and interferon-beta, the researchers reported January 10 in Nature Communications.

But the question is still open about whether remdesivir canstop the new coronavirus.

In lab tests, it can. Both remdesivir and the antimalaria drug chloroquine inhibited the new viruss ability to infect and grow in monkey cells, virologist Manli Wang of the Wuhan Institute of Virology of the Chinese Academy of Sciences and colleagues reported February 4 in Cell Research. Remdesivir also stopped the virus from growing in human cells. Chloroquine can block infections by interfering with the ability of some viruses including coronaviruses to enter cells. Wang and colleagues found that the drug could also limit growth of the new coronavirus if given after entry. Chloroquine also may help the immune system fight the virus without the kind of overreaction that can lead to organ failure, the researchers propose.

In China, remdesivir is already being tested in patients. And NIAID announced February 25 that it had launched a clinical trial of remdesivir at the University of Nebraska Medical Center in Omaha. The first enrolled patient was an American evacuated from the Diamond Princess cruise ship in Japan that had been quarantined in February because of a COVID-19 outbreak.

Ultimately, nearly 400 sick people at 50 centers around theworld will participate in the NIAID trial, which will compare remdesivir with aplacebo. The trial may be stopped or altered to add other drugs depending onresults from the first 100 or so patients, says Andre Kalil, an infectiousdisease physician at the University of Nebraska Medical Center.

Researchers considered many potential therapies, but basedon results from the animal and lab studies, remdesivir seemed to be the onethat was more promising, Kalil says.

In the early patient studies, figuring out when to give remdesivirto patients might not be easy, Sheahan says. Often drugs are tested on thesickest patients. For example, those in the NIAID trial must have pneumonia toparticipate. By the time someone lands in the intensive care unit withCOVID-19, it may be too late for remdesivir to combat the virus, Sheahan says.It may turn out that the drug works best earlier in the disease, before viralreplication peaks.

We dont know because it hasnt really been evaluated inpeople how remdesivir will work, or if it will work at all, Sheahan cautions.

The drug seems to have helped a 35-year-old man in Snohomish County, Wash., researchers reported January 31 in the New England Journal of Medicine. The man had the first confirmed case of COVID-19 in the United States. He developed pneumonia, and doctors treated him with intravenous remdesivir. By the next day, he was feeling better and was taken off supplemental oxygen.

Thats just one case, and the company that makes remdesivirhas urged caution. Remdesivir is not yet licensed or approved anywhereglobally and has not been demonstrated to be safe or effective for any use,the drugs maker, biopharmaceutical company Gilead Sciences, headquartered inFoster City, Calif., said in a statement on January 31.

But global health officials are eager to see the drug testedin people. Theres only one drug right now that we think may have realefficacy, and thats remdesivir, WHOs assistant director-general BruceAylward said during a news briefing on February 24. But researchers in Chinaare having trouble recruiting patients into remdesivir studies, partly becausethe number of cases has been waning and partly because too many trials ofless-promising candidates are being offered. We have got to start prioritizingenrollment into those things that may save lives and save them faster, Aylwardsaid.

Another strategy for combating COVID-19 involves distracting the virus with decoys. Like the SARS virus, the new virus enters human cells by latching on to a protein called ACE2. The protein studs the surface of cells in the lungs and many other organs. A protein on the surface of the new virus binds to ACE2 10 to 20 times as tightly as the SARS protein does.

Researchers at Vienna-based Apeiron Biologics announced February 26 that they would use human ACE2 protein in a clinical trial against the new coronavirus. When released into the body, the extra ACE2 acts as a decoy, glomming on to the virus, preventing it from getting into cells.

ACE2 isnt just a viruss doorway to infection. Normally, it helps protect the lungs against damage, says Josef Penninger, an immunologist at the University of British Columbia in Vancouver and a cofounder of Apeiron. Penninger and colleagues reported the proteins protective qualities, based on studies with mice, in Nature in 2005.

During a viral infection, the protein is drawn away from thecell surface and cant offer protection. Penninger thinks that adding in extraACE2 may help shield the lungs from damage caused by the virus and by immunesystem overreactions. The protein is also made in many other organs. Penningerand colleagues are testing whether the new virus can enter other tissues, whichmight be how the virus leads to multiple organ failures in severely ill people.

The decoy protein drug, called APN01, has already beenthrough Phase I and Phase II clinical testing. We know its safe, Penningersays. Now researchers just need to determine whether it works.

No one knows whether any of these approaches can help stemthe spread of COVID-19.

Right now, we need lots of people working with lots ofideas, Satchell says. Similarities between the viruses that cause SARS andCOVID-19 may mean that some drugs could work against both. There is a hopethat several small molecules that were identified as inhibitors of the SARSprotease would represent reasonable starting points for trying to make a drugfor the 2019 coronavirus, Burley says.

The open questionis, can you produce a drug that is both safe and effective quickly enough tohave an impact? SARS was stopped by traditional infection-control measures in2004, before any virus-fighting drugs made it through the development pipeline.

But had a decision been made then to spend $1 billion tomake a safe and effective drug against SARS, Burley says, such a drug might beworking now against the new coronavirus, eliminating the need to spend hundredsof billions of dollars to contain this new infection.

An investment in SARS would not have paid off for peoplewith MERS, which is still a danger in the Middle East. The MERS virus is toodifferent from SARS at the RNA level for SARS drugs to work against it.

But a future coronavirus might emerge that is similar enough to SARS and SARS-CoV-2 to be worth the cost, Burley says. Even if the current outbreak dwindles and disappears, he says, governments and companies should keep investing in drugs that can stop coronaviruses.

Im quite certain that the economic impact of the epidemic is going to run into the hundreds of billions, he says. So you would only need a 1 percent chance of something that was treatable with the drug to show up in the future to have made a good investment.

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