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Genes May Hold Key To New Treatments For Covid-19 Infections

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

A new multicenter study from the UK sheds more light and brings the promise of new treatments. Dr. Kenneth Baillie, a critical care specialist at the University of Edinburgh’s Roslin Institute, is the project’s chief investigator. 

Their discovery, just published in Nature, came to my attention in a remarkably clear Twitter explainer that began:

Baillie then explains how using genetics can help find targeted 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, “Your 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.

At this one position, if you have a "T" instead of a "C", then your odds of life-threatening Covid-19 are 1.3x greater.

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 one change makes a difference to how much of the TYK2 gene you make. So we can ask, if you make more TYK2, are you more at risk?

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

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

This demonstrates the beauty of genetics for drug target discovery. Faced with a new disease, that we didn't understand at all, we can look across the *entire* code that makes our immune system, to find the exact points we need to target with drugs, in order to save lives.”

This thread is a stellar example of effective science communication.

This multi-center study is also remarkable for having been done within only six months and for the sheer number of collaborating centers. There were 208 ICUs across the UK which already have enrolled 2700 critically ill patients in this study to examine their genes.

The related GenOMICC (Genetics Of Mortality In Critical Care) repository has 6685 people thus far. They are looking to compare the genes of those critically ill with Covid-19 to those who had a very mild course. To detect a “real” difference, the participants must be matched by many other factors. GenOMICC is hoping for 15,000 participants. You can see more here:

Having been a principal investigator on several sepsis trials in the past, I am astonished at the rapid enrollment of patients and at the level of cooperation that enabled this study and quick results.

There are different roles for other genes

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

Another study showed antibodies to interferon were found in 10% of critically ill patients, almost all of whom were men. This suggests perhaps one reason why men have worse outcomes. But treatment with interferon in the WHO’s “Solidarity” trial did not show benefit—was that because it was given too late in the course of disease?

TYK2 is one gene that showed differences in those with severe Covid-19. When the gene’s expression goes into overdrive, TYK2 can cause serious lung damage from the inflammatory response. Eli Lilly has an antiarthritis drug, baricitinib (Olumiant), which blocks this gene. This drug, part of a class called JAK inhibitors, received an Emergency Use Authorization (EUA) last month for use in combination with remdesivir to reduce the length of hospitalization. It only showed a modest effect and did not reduce the death rate.

Later life-threatening illness, with marked lung inflammation, is a 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 that driven by DPP9, TYK2, and CCR2 — reduced deaths for those in this later stage of infection, but not those treated early.

These two examples show that this genetic sleuthing can identify likely targets for drug therapy. But, “We won't know whether these approaches work until we have large scale randomized trials,” Baillee stresses.

Drugs that target CCR2 are already being used for psoriasis.

Why is this important? 

Dr. Baillie stressed that finding these specific genes associated with severe Covid-19 infections points to potential treatments. Furthermore, the research will be faster if you can use “repurposed” drugs—those are drugs already marketed for another disease, like baricitinib.

This type of approach has already been used by Dr. David Fajgenbaum, Founding Director of the Center for Cytokine Storm Treatment & Laboratory at the University of Pennsylvania (among others). He is also a patient with idiopathic multicentric Castleman disease (iMCD). Fajgenbaum was critically ill and dying from iMCD. When he was able to work during remissions, he was able to identify the genes and proteins involved in his disease and the pathways causing his illness. He identified that his levels of markers of the mTOR rose significantly in the weeks leading up to each of his relapses. Through that research, he was able to discover that an old drug called sirolimus would block the specific gene at fault. It inhibits the production of mTOR, and ultimately,  saved his life. His approach has since been used to look for similar signaling pathways for other patients and diseases.

Fajgenbaum also has a registry from an extensive literature review, “CORONA,” for drugs repurposed to try to treat Covid-19. He is sharing that with another database, CURE ID, in which the FDA and NCATS are collecting case reports of already marketed drugs being used for Covid-19. It is hoped that identification of these promising existing drugs will help inform further clinical trials more quickly. (Disclosure: I am on the advisory board of CURE ID).

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

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