Genes May Be Key to New Treatments for Covid-19 Infections

Why do some people have no symptoms of a Covid-19 infection and others quickly become septic, develop respiratory failure, and die? We’ve only had a few clues: age, gender, and weight are stark indicators of trouble.

A new multicenter study from the UK sheds more light and brings the promise of new treatments. Dr Kenneth Baillie, an intensive care specialist at the Roslin Institute at the University of Edinburgh, is the principal investigator on the project.

His discovery, just published in Nature, caught my eye in a remarkably clear Twitter explanation that began:

Baillie then explains how the use of genetics can help find specific new therapies. In this case, they found five genes (called LZTFL1, OAS1, DPP9, TYK2, and IFNAR2) that were markedly different between ICU patients and volunteers who did not have Covid-19. He continues: “His DNA is a long code, which we represent as the letters A, C, T and G. There are 3,000,000,000 letters in the code to make a human being.

In this position, if you have a “T” instead of a “C,” then your chances of a life-threatening Covid-19 are 1.3 times higher.

It doesn’t sound like much, and compared to the effect of age on risk, it isn’t. But that’s not why it matters.

That change makes a difference in the amount of the TYK2 gene you make. So we can ask, if you do more TYK2, Are you more at risk?

The answer is yes. Less TYK2 it is associated with a lower risk. That suggests that a drug that inhibits TYK2 it could make people less likely to develop life-threatening Covid-19-19. The good news is that we have a whole class of drugs that do this (JAK inhibitors).

The other genes we found suggest other treatments, which we discuss in the article. We already know that genetic evidence doubles the probability that a drug will be successful.

This shows the beauty of genetics for the discovery of drug targets. Faced with a new disease, which we did not understand at all, we can search the * complete * code that makes up our immune system, to find the exact points that we must attack with life-saving drugs ”.

This thread is a stellar example of effective science communication.

This multicenter study is also notable for having been carried out in just six months and for the large number of collaborating centers. There were 208 ICUs across the UK who had already enrolled 2700 critically ill patients in this study to examine your genes.

The related repository GenOMICC (Genetics Of Mortality In Critical Care) has 6685 people so far. They seek to compare the genes of critically ill patients with Covid-19-19 with those of those who had a very mild course. To detect a “real” difference, participants must agree on many other factors. GenOMICC expects 15,000 participants. You can see more here:

Having been a principal investigator on several sepsis trials in the past, I am in awe of the rapid patient enrollment and level of cooperation that this study and rapid results allowed.

There are different roles for other genes.

In addition to TYK2, A different gene, IFNAR2, encodes interferon receptors, which elicit an immune response to viruses. the IFNAR2 and OAS genes are important in the initial viral defense response in early infection.

Another study showed that antibodies to interferon were found in 10% of critically ill patients, almost all men. This suggests perhaps one reason why men perform worse. But the interferon treatment in the WHO “Solidarity” trial showed no benefit, was that because it was given too late in the course of the disease?

TYK2 it is a gene that showed differences in those with severe Covid-19. When gene expression is accelerated, TYK2 it can cause severe lung damage due to the inflammatory response. Eli Lilly has an anti-arthritis drug, baricitinib (Olumiant), that blocks this gene. This drug, part of a class called HOW inhibitors, received an emergency use authorization (EUA) last month for use in combination with remdesivir to reduce the length of hospital stay. It only showed a modest effect and did not reduce the mortality rate.

The subsequent life-threatening disease, with marked lung inflammation, is the result of the person’s response to infection and is driven by other genes. The large “recovery” trial showed that dexamethasone, a steroid that reduces inflammation, such as the one that causes DPP9, TYK2 and CCR2 – Reduction in deaths of those who are in this last stage of the infection, but not of those who receive early treatment.

Targeting drugs CCR2 they are already being used for psoriasis.

Why is this important?

Dr. Baillie emphasized that finding these specific genes associated with severe Covid-19-19 infections points to potential treatments. Also, research will be faster if you can use “repurposed” drugs, which are already marketed for another disease, such as baricitinib.

This type of approach has already been used by Dr. David Fajgenbaum, Founding Director of the University of Pennsylvania Cytokine Storm Laboratory and Treatment Center (among others). He is also a patient with idiopathic multicentric Castleman disease (iMCD). Fajgenbaum was seriously ill and dying from iMCD. When he was able to work through remissions, he was able to identify the genes and proteins involved in his disease and the pathways that cause it. He identified that their mTOR marker levels increased significantly in the weeks leading up to each of their relapses. Through that research, he was able to discover that an ancient drug called sirolimus would block the specific culprit gene. It inhibits mTOR production and ultimately saved his life. Since then, his approach has been used to search for similar signaling pathways for other patients and diseases.

Fajgenbaum also has a record of an extensive literature review, “CORONA”, for repurposed drugs to try to treat Covid-19. He is sharing that with another database, CURE ID, in which the FDA and NCATS are compiling case reports of already marketed drugs being used for Covid-19. The identification of these promising existing drugs is expected to help inform additional clinical trials more quickly.

Baillie concluded our interview by explaining: “It is becoming clear… that critical illness in Covid-19-19 is an inflammatory disease and that to treat it, we must target very specific parts of the immune system to give our patients the best chance of survival. . And genetics leads us to those very specific parts of the immune system that we need to target. “