By Sascha Karberg
It’s just a tiny, nondescript molecule – and yet it’s the cause of the biggest global crisis in a long time. Researchers call it “ACE-2,” a protein that sits in the membrane of many human cells that line the airways and lung tissue. It is this ACE-2 that makes infection with Sars-CoV-2, the new coronavirus, possible. It is the gateway for viruses to enter the cell, where they multiply. It is also related to ACE-2 that some patients become particularly seriously ill or even die from acute lung and multiple organ failure.
But as paradoxical as it may sound, at the same time ACE-2 could be the salvation, the cure, for these very patients. At least that’s what the researchers at a Viennese biotech company hope to start a study in Germany, Denmark and Austria. Covid-19 patients are to be injected with large amounts of artificial ACE-2.
An old idea that could now save lives
The story begins in 2002 when the first new type of corona virus in China probably leapt from crawl cats to humans, infected about 80,000, made sick and killed almost 800: Sars-CoV-1. Even if it differed in some properties from today’s virus – for example in that infected people developed symptoms very quickly and not only after about two or three days – it also used ACE-2 as a gateway into the cells.
Back then, Viennese researcher Josef Penninger was researching Sars-CoV-1, which, like all corona viruses, has a shell that is littered with “sting” proteins that look like a crown or a corona in solar eclipse on electron microscopic images. When the molecular biologist, then head of the Institute of Molecular Biotechnology in Vienna, examines this “sting” in more detail, he realizes that it fits like a key into the “lock” of the ACE-2 molecule in the membrane of lung cells and the cell unlocked for the virus.
This gave him an idea: if the coronavirus-infected patient were to be given masses of artificial ACE-2, they would have to defuse the virus spines like marshmallows the thorns of a cactus. There would hardly be any viruses left to infect new cells.
Sars-CoV-2 is very similar to Sars-CoV-1
So in 2005 Penninger founded a company, Apeiron, which developed “APN01”, the ACE-2 imitation. But the Sars epidemic is over two years ago, and after the initial collaboration and support, the British pharmaceutical company Glaxo-Smith-Kline withdraws from the cooperation with Apeiron, the money flows into other projects. Apeiron’s researchers can prove in five studies with a total of 89 patients that APN01 is tolerable and does not cause any serious side effects. But the last study with APN01 will take place in 2009. It is not enough for proof of effectiveness or even approval. You switch to cancer drugs. But when it becomes clear in January 2020 that a corona virus is once again being used in China, Apeiron’s researchers see an opportunity to revive the old concept.
“In early February, we saw that Sars-CoV-2 is very similar to the 2002 Sars virus,” said Peter Llewellyn-Davies from the company management. Above all, the structure of the spike protein, i.e. the sting of the virus, is practically identical at 76 percent agreement at the crucial points. Studies have shown that the stinger of Sars-CoV-2 binds to ACE-2 even better than the old Sars virus.
“At that time, however, the virus was only widespread in China, so we wanted to launch a study there quickly and test APN01 there in a study with a total of 24 patients.” But talks with the Chinese authorities are delayed, and the epidemic is on its way , jumps to other countries, becomes a pandemic. “Then we decided to do a larger study in Europe right away.”
Do coronaviruses also infect the gut?
At a total of ten clinics in Germany, Austria and Denmark, 200 Covid-19 patients are to be recruited, half of whom will receive the medication and the other placebo to test whether it works. “Many centers can be considered, including clinics in Italy,” says Llewellyn-Davies. “But the investigators are also so busy there that they cannot supervise any additional clinical studies.”
The ACE-2 imitation is injected into the patient and not only gets into the lung tissue, but also into other organs, such as the intestine. There too, the cells carry ACE-2 receptors to absorb nutrients. The viruses can also invade there. An explanation for the diarrhea symptoms described in some Covid 19 patients? “The infection could have started here because food was eaten from the Wuhan market, probably the origin of the outbreak,” wrote the Penninger research team, who is now researching at the University of Toronto, in early March in the journal “Intensive Care Medicine”.
Apeiron expects the results of the study “in the fourth quarter” of 2020. Llewellyn-Davies cannot predict how quickly an approval can be given – provided that there is convincing proof of effectiveness. Because currently the usual speed of work of the regulatory authorities seems to be accelerating drastically. “I have been in this industry for a long time, but I have never seen a study approved by the authorities in Austria, Germany and Denmark within 14 days.” That was “incredible”.
“Covid-19 will remain an issue for a long time to come”
The authorities cannot help in the manufacture of the active ingredient, Apeiron is trying to organize this in cooperation with large pharmaceutical companies. Whether the active ingredient – provided it works as hoped – will still come in time to help patients in this pandemic is open. “We don’t know how long this pandemic will continue,” says Llewellyn-Davies. “They are now trying to limit the spread, but I still assume that Covid 19 disease will remain an issue for a long time to come.”
