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First Mice Engineered to Survive COVID-19 Are Like Young, Healthy … – NYU Langone Health

Researchers have genetically engineered the first mice that get a humanlike form of COVID-19, according to a study published online November 1 in Nature.

Led by researchers from NYU Grossman School of Medicine, the new work created lab mice with human genetic material for ACE2a protein snagged by the pandemic virus so that it can attach to human cells as part of the infection. The mice with this genetic change developed symptoms similar to those of young humans infected with the virus causing COVID-19, instead of dying upon infection, as had occurred with prior mouse models.

That these mice survive creates the first animal model that mimics the form of COVID-19 seen in most peopledown to the immune system cells activated and comparable symptoms, said senior study author Jef D. Boeke, PhD, the Sol and Judith Bergstein Director of the Institute for Systems Genetics at NYU Langone Health. This has been a major missing piece in efforts to develop new drugs against this virus.

Given that mice have been the lead genetic model for decades, added Dr. Boeke, there are thousands of existing mouse lines that can now be crossbred with our humanized ACE2 mice to study how the body reacts differently to the virus in patients with diabetes or obesity, or as people age.

The new study revolves around a new method to edit DNA, the 3 billion letters of the genetic code that serve as instructions for building our cells and bodies.

While famous techniques like CRISPR enable editing DNA just one or a few letters at a time, some challenges require changes throughout genes that can be up to 2 million letters long. In such cases, it may be more efficient to build DNA from scratch, with far-flung changes made in large swaths of code preassembled and then swapped into a cell in place of its natural counterpart. Because human genes are so complex, Dr. Boekes lab first developed its genome writing approach in yeast, one-celled fungi that share many features with human cells but that are simpler and easier to study.

More recently, Dr. Boekes team adapted their yeast techniques to the mammalian genetic code, which is made up not only of genes that encode proteins but also of many switches that turn on different genes at different levels in different cell types. By studying this poorly understood dark matter that regulates genes, the research team was able to design for the first time living mice with cells that had more humanlike levels of ACE gene activity. The study authors used yeast cells to assemble DNA sequences of up to 200,000 letters in a single step, and then delivered these naked DNAs into mouse embryonic stem cells using their new delivery method, mSwAP-In.

Overcoming the size limits of past methods, mSwAP-In delivered a humanized mouse model of COVID-19 pathology by overwriting 72 kilobases (kb) of mouse Ace2 code with 180 kb of the human ACE2 gene and its regulatory DNA. To accomplish this cross-species swap, the study method cut into a key spot in the DNA code around the natural gene, swapped in a synthetic counterpart in steps, and with each addition, added a quality control mechanism so that only cells with the synthetic gene survived. The research team then worked with Sang Y. Kim, PhD, at NYU Langones Rodent Genetic Engineering Laboratory, using a stem cell technique called tetraploid complementation to create a living mouse whose cells included the overwritten genes.

In addition, the researchers had previously designed a synthetic version of the gene Trp53, the mouse version of the human gene TP53, and swapped it into mouse cells. The protein encoded by this gene coordinates the cells response to damaged DNA, and it can even instruct cells containing it to die to prevent the buildup of cancerous cells. When this guardian of the genome itself becomes faulty, it turns into a major contributor to human cancers.

Whereas the ACE2 experiments had swapped in an unchanged version of a human gene, the synthetic, swapped-in Trp53 gene had been designed to no longer include a combination of molecular code letterscytosine (C) next to guanine (G)known to be vulnerable to random cancer-causing changes. The researchers overwrote key CG hot spots with code containing a different DNA letter, adenine (A).

The AG switch left the genes function intact, but lessened its vulnerability to mutation, with the swap predicted to lead to a ten- to fiftyfold lower mutation rate, said first author Weimin Zhang, PhD, a postdoctoral scholar in Dr. Boekes lab. Our goal is to demonstrate in a living test animal that this swap leads to fewer mutations and fewer resulting tumors, and those experiments are being planned.

Along with Dr. Boeke and Dr. Zhang, NYU Langone study authors were Ran Brosh, PhD; Aleksandra Wudzinska, MPhil; Yinan Zhu; Noor Chalhoub; Emily Huang; and Hannah Ashe in the Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology; Ilona Golynker; Luca Carrau, PhD; Payal Damani-Yokota, PhD; Camille Khairallah, PhD; Kamal M. Khanna, PhD; and Benjamin tenOever, PhD; in the Department of Microbiology; and Matthew T. Maurano and Dr. Kim in the Department of Pathology.

The work was funded by National Institutes of Health CEGS grant 1RM1HG009491 and Perlmutter Cancer Center Support Grant P30CA016087. Dr. Boeke is a founder of CDI Labs Inc., a founder of Neochromosome Inc., a founder of ReOpen Diagnostics LLC, and serves or has served on the scientific advisory boards of Logomix Inc., Modern Meadow, Rome Therapeutics, Sample6, Sangamo Therapeutics, Tessera Therapeutics, and the Wyss Institute. Dr. Boeke also receives consulting fees and royalties from Opentrons and holds equity in the company. These relationships are managed in accordance with the policies of NYU Langone Health.

Greg Williams Phone: 212-404-3500 Gregory.Williams@NYULangone.org

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First Mice Engineered to Survive COVID-19 Are Like Young, Healthy ... - NYU Langone Health

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Scientists are narrowing in on why some people keep avoiding Covid. BA.5 could end that luck. – NBC News

A majority of people in the U.S have had Covid-19 at least once likely more than 70% of the country, White House Covid-19 Response Coordinator Ashish Jha said on Thursday, citing data from the Centers for Disease Control and Prevention.

Many have been infected multiple times. In a study that has not been peer viewed that looked at 257,000 U.S. veterans who'd contracted Covid at least once, 12% had a reinfection by April and about 1% had been infected three times or more.

This raises an obvious question: What is keeping that shrinking minority of people from getting sick?

Disease experts are homing in on a few predictive factors beyond individual behavior, including genetics, T cell immunity and the effects of inflammatory conditions like allergies and asthma.

But even as experts learn more about the reasons people may be better equipped to avoid Covid, they caution that some of these defenses may not hold up against the latest version of omicron, BA.5, which is remarkably good at spreading and evading vaccine protection.

"It really takes two to tango," said Neville Sanjana, a bioengineer at the New York Genome Center. "If you think about having an infection and any of the bad stuff that happens after that, it really is a product of two different organisms: the virus and the human."

In 2020, New York University researchers identified a multitude of genes that could affect a person's susceptibility to the coronavirus. In particular, they found that inhibiting certain genes that code for a receptor known as ACE2, which allows the virus to enter cells, could reduce a person's likelihood of infection.

Sanjana, who conducted that research, estimated that about 100 to 500 genes could influence Covid-19 susceptibility in sites like the lungs or nasal cavity.

Genetics is "likely to be a large contributor" to protection from Covid-19, he said. "I would never say its the only contributor."

In July, researchers identified a common genetic factor that could influence the severity of a coronavirus infection. In a study of more than 3,000 people, two genetic variations decreased the expression of a gene called OAS1, which is part of the innate immune response to viral infections. That was associated with an increased risk of Covid-19 hospitalization.

Increasing the gene's expression, then, should have the opposite effect reducing the risk of severe disease though it wouldn't necessarily prevent infection altogether.

"Its very natural to get infected once you are exposed. Theres no magic bullet for that. But after you get infected, how youre going to respond to this infection, thats what is going to be affected by your genetic variants," said Ludmila Prokunina-Olsson, the study's lead researcher and chief of the Laboratory of Translational Genomics at the National Cancer Institute.

Still, Benjamin tenOever, a microbiology professor at the NYU Grossman School of Medicine who helped conduct the 2020 research, said it would be difficult for scientists to pinpoint a particular gene responsible for preventing a Covid infection.

"While there might still be certainly some genetics out there that do render people completely resistant, theyre going to be incredibly hard to find," tenOever said. "People have already been looking intensely for two years with no actual results."

Aside from this new coronavirus, SARS-CoV-2, four other coronaviruses commonly infect people, typically causing mild to moderate upper respiratory illnesses like the common cold.

A recent study suggested that repeated exposure to or occasional infections from these common cold coronaviruses may confer some protection from SARS-CoV-2.

The researchers found that T cells, a type of white blood cell that recognizes and fights invaders, seem to recognize SARS-CoV-2 based on past exposure to other coronaviruses. So when a person who has been infected with a common cold coronavirus is later exposed to SARS-CoV-2, they might not get as sick.

But that T cell memory probably can't prevent Covid entirely.

"While neutralizing antibodies are key to prevent an infection, T cells are key to terminate an infection and to modulate the severity of infection," said Alessandro Sette, the studys author and a professor at the La Jolla Institute for Immunology.

Sette said it's possible that some people's T cells clear the virus so quickly that the person never tests positive for Covid. But researchers aren't yet sure if that's what's happening.

"Its possible that, despite being negative on the test, it was a very abortive, transient infection that was not detected," Sette said.

At the very least, he said, T cells from past Covid infections or vaccines should continue to offer some protection against coronavirus variants, including BA.5.

Although asthma was considered a potential risk factor for severe Covid earlier in the pandemic, more recent research suggests that low-grade inflammation from conditions like allergies or asthma may have a protective benefit.

"Youll hear these stories about some individuals getting sick and having full-blown symptoms of Covid, and having slept beside their partner for an entire week during that period without having given it to them. People think that they must have some genetic resistance to it, [but] a big part of that could be if the partner beside them in any way has a higher than normal inflammatory response going on in their lungs," tenOever said.

A May study found that having a food allergy halved the risk of a coronavirus infection among nearly 1,400 U.S. households. Asthma didn't lower people's risk of infection in the study, but it didn't raise it, either.

One theory, according to the researchers, is that people with food allergies express fewer ACE2 receptors on the surface of their airway cells, making it harder for the virus to enter.

"Because there are fewer receptors, you will have either a much lower grade infection or just be less likely to even become infected," said Tina Hartert, a professor of medicine and pediatrics at the Vanderbilt University School of Medicine, who co-led that research.

The study took place from May 2020 to February 2021, before the omicron variant emerged. But Hartert said BA.5 likely wouldn't eliminate cross-protection from allergies.

"If something like allergic inflammation is protective, I think it would be true for all variants," Hartert said. "The degree to which it could be protective could certainly differ."

For many, the first explanation that springs to mind when thinking about Covid avoidance is one's personal level of caution. NYU's TenOever believes that individual behavior, more than genetics or T cells, is the key factor. He and his family in New York City are among those who've never had Covid, which he attributes to precautions like staying home and wearing masks.

"I dont think for a second that we have anything special in our genetics that makes us resistant," he said.

It's now common knowledge that Covid was easier to avoid before omicron, back when a small percentage of infected people were responsible for the majority of the virus's spread. A 2020 study, for example, found that 10% to 20% of infected people accounted for 80% of transmissions.

But omicron and its subvariants have made any social interaction riskier for everyone involved.

"It's probably far more of an equal playing field with the omicron variants than it ever was for the earlier variants," tenOever said.

BA.5, in particular, has increased the odds that people who've avoided Covid thus far will get sick. President Joe Biden is a prime example: He tested positive for the first time this week.

But even so, Jha said on Thursday in a news briefing, "I dont believe that every American will be infected."

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Scientists are narrowing in on why some people keep avoiding Covid. BA.5 could end that luck. - NBC News

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Gene experts claim they identified human genes that can protect against Covid-19 – CNBC

COVID-19 Coronavirus molecule, March 24, 2020.

CDC | API | Gamma-Rapho via Getty Images

A team of CRISPR scientists at the New York Genome Center, New York University and Icahn School of Medicine at Mount Sinai say they have identified the genes that can protect human cells against Covid-19, a disease that has infected over 40 million and led to 1 million deaths worldwide. The discovery comes after an eight-month screen of all 20,000 genes in the human genome led by Dr. Neville Sanjana at the New York Genome Center. Leading virologist at Mount Sinai, Dr. Benjamin tenOever, developed a series of human lung cell models for the coronavirus screening to better understand immune responses to the disease and co-authored the study.

Their study, published online last month by Cell, will appear in the scientific peer-reviewed journal's Jan. 7 print issue.

The goal was two-fold: to identify the genes that make human cells more resistant to SARS-CoV-2 virus; and test existing drugs on the market that may help stop the spread of the disease.

The breakthrough comes at a time when drug makers such as Pfizer, Oxford-AstraZeneca and Moderna are fast-forwarding vaccine and therapeutics to treat Covid-19. On Friday, Pfizer and BioNTech requested emergency authorization from the FDA for their Covid vaccine that contains genetic material called messenger RNA, which scientists expect provokes the immune system to fight the virus.

In order to better understand the complex relationships between host and virus genetic dependencies, the team used a broad range of analytical and experimental methods to validate their results. This integrative approach included genome editing, single-cell sequencing, confocal imaging and computational analyses of gene expression and proteomic datasets.

After intensive research the scientists and doctors claim they have found 30 genes that block the virus from infecting human cells including RAB7A, a gene that seems to regulate the ACE-2 receptor that the virus binds to and uses to enter the cell. The spike protein's first contact with a human cell is through ACE-2 receptor.

"Our findings confirmed what scientists believe to be true about ACE-2 receptor's role in infection; it holds the key to unlocking the virus," said Dr. tenOever. "It also revealed the virus needs a toolbox of components to infect human cells. Everything must be in alignment for the virus to enter human cells."

The team discovered that the top-ranked genes those whose loss reduces viral infection substantially clustered into a handful of protein complexes, including vacuolar ATPases, Retromer, Commander, Arp2/3, and PI3K. Many of these protein complexes are involved in trafficking proteins to and from the cell membrane.

"We were very pleased to see multiple genes within the same family as top-ranked hits in our genome-wide screen. This gave us a high degree of confidence that these protein families were crucial to the virus lifecycle, either for getting into human cells or successful viral replication," said Dr. Zharko Daniloski, a postdoctoral fellow in the Sanjana Lab and co-first author of the study.

Using proteomic data, they found that several of the top-ranked host genes directly interact with the virus's own proteins, highlighting their central role in the viral lifecycle. The team also analyzed common host genes required for other viral pathogens, such as Zika or H1N1 pandemic influenza.

The research team also identified drugs that are currently on the market for different diseases that they claim block the entry of Covid-19 into human cells by increasing cellular cholesterol. In particular, they found three drugs currently on the market were more than 100-fold more effective in stopping viral entry in human lung cells:

The other five drugs that were tested called PIK-111, Compound 19, SAR 405, Autophinib, ALLN -- are used in research but are not yet branded and used in clinical trials for existing diseases.

Our findings confirmed what scientists believe to be true about ACE-2 receptor's role in infection; it holds the key to unlocking the virus.

Their findings offer insight into novel therapies that may be effective in treating Covid-19 and reveal the underlying molecular targets of those therapies.

The bioengineers in New York were working on other projects with gene-editing technology from CRISPR but quickly pivoted to studying the coronavirus when it swept through the metropolitan area last March. "Seeing the tragic impact of Covid-19 here in New York and across the world, we felt that we could use the high-throughput CRISPR gene editing tools that we have applied to other diseases to understand what are the key human genes required by the SARS-CoV-2 virus," said Dr. Sanjana.

Dr. Neville Sanjana and his team at the New York Genome Center used CRISPR to identify the genes that can protect human cells against Covid-19.

New York Genome Center

As he explained, "current treatments for SARS-CoV-2 infection currently go after the virus itself, but this study offers a better understanding of how host genes influence viral entry and will enable new avenues for therapeutic discovery."

Previously, Dr. Sanjana has applied genome-wide CRISPR screens to identify the genetic drivers of diverse diseases, including drug resistance in melanoma, immunotherapy failure, lung cancer metastasis, innate immunity, inborn metabolic disorders and muscular dystrophy.

"The hope is that the data from this study which pinpoints required genes for SARS-CoV-2 infection could in the future work be combined with human genome sequencing data to identify individuals that might be either more susceptible or more resistant to COVID-19," Dr. Sanjana said.

The New York team is not the first to use CRISPR gene editing techniques to fight Covid-19. Other bioengineering groups at MIT and Stanford have been using CRISPR to develop ways to fight the SARS-CoV-2 and develop diagnostic tools for Covid-19.

The potential for using CRISPR to eliminate viruses has already generated some enthusiasm in the research community. Last year, for example, Excision BioTherapeuticslicenseda technology from Temple University that uses CRISPR, combined with antiretroviral therapy, to eliminate HIV, the virus that causes AIDS.

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What determines whether you’ll develop a mild or severe case of Covid-19? It might be in your genes. – The Daily Briefing

While most people who contract the new coronavirus develop a mild case of Covid-19, for some the disease is deadlyand researchers are exploring whether a person's DNA may play a role in determining the disease's severity.

How Dignity Health keeps patients connected to telegeneticsduring and beyond Covid-19

Researchers already have determined that a person's age and whether they have certain underlying health conditions can affect their risk of developing a severe case of Covid-19, the disease caused by the new coronavirus. But now, some research suggests a person's blood type may be another factor in whether they have a higher risk of developing a severe case of the disease.

For example, a preprint study published Tuesday that has not been peer-reviewed examined blood samples from 1,610 Covid-19 patients who developed severe cases of Covid-19, which the researchers classified as needing oxygen or a ventilator as part of their treatment. The researchers sequenced part of each those patients' genomes, and then performed the same analysis on samples from 2,205 blood donors who did not have Covid-19 and compared the results.

The researchers found that many of the patients who had severe cases of Covid-19 possessed the same variant on a gene that determines a person's blood type. Specifically, the researchers found that having blood type A was linked with a 50% increase in the likelihood a patient would develop a severe case of Covid-19.

According to the New York Times, a separate preprint study conducted by researchers in China that hasn't yet been peer-reviewed found similar results. The study found that, out of 2,173 Covid-19 patients with different blood types, blood type A was associated with a higher risk of death from Covid-19 when compared with other blood types. The study also found that people with blood type A appeared more likely to contract the new coronavirus, whereas those with blood type O appeared to be the least likely to contract the virus.

Andre Franke, a molecular geneticist at the University of Kiel in Germany, who led the first study said he and his colleagues also identified another locus on Chromosome 3 that appeared to be linked with Covid-19. However, the researchers noted that locus hosts six different genes, and they've yet to determine which of those genes influences how Covid-19 develops.

Despite the findings, Franke said researchers are still unsure exactly how a person's blood type plays a part in how Covid-19 affects them. "That is haunting me, quite honestly," he said.

Franke said the locus that hosts the blood-type gene also contains a portion of a person's DNA that controls a gene that makes a protein that generates robust immune responses, the Times reports. According to the Times, researchers and providers have found that the new coronavirus can trigger a so-called "cytokine storm" in some patients, which occurs when a patient's immune system overreacts to a pathogen and damages a patient's organs, and it's "theoretically possible that genetic variations influence that response."

For a separate study published last month in Cell, researchers looked into how the new coronavirus affects human cells and found that, within three days of infection, the virus activates genes in the cells that produce cytokine proteins, which are the proteins that can cause cytokine storm. At the same time, the virus blocks genes in the cells that produce interferons that could constrain the virus' replicationsomething most other viruses don't do, according to Benjamin tenOever of the Icahn School of Medicine at Mount Sinai, who co-authored the study. "It's something I have never seen in my 20 years of" studying viruses, he said.

tenOever explained that, without interferons, "there is nothing to stop the virus from replicating and festering in the lungs forever."

According to STAT News, the researchers' findings could help scientists identify treatments for Covid-19. For instance, Vineet Menachery from the University of Texas Medical Branch said providing high-risk patients with interferons could potentially "allow treated cells to fend off the virus better and limit its spread."

But more research on how genetic variants might affect Covid-19 are needed, according to Jonathan Sebat, a geneticist at the University of California-San Diego who was not involved in the studies. According to Sebat, previous studies attempting to identify variances in genetic loci that are significantly more common in sick people than healthy people have failed, meaning it's possible that the variants identified in the recent studies may not play as much as a role as in how Covid-19 develops as the new findings may imply (Zimmer, New York Times, 6/3; Begley, STAT News, 5/21; Mangin, Scientific American, 4/30).

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What determines whether you'll develop a mild or severe case of Covid-19? It might be in your genes. - The Daily Briefing

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30+ genes identified that could protect us from COVID, opening door to gene therapy prevention solutions – Genetic Literacy Project

The goal was two-fold: to identify the genes that make human cells more resistant to SARS-CoV-2 virus; and test existing drugs on the market that may help stop the spread of the disease.

The breakthrough comes at a time whendrug makers such as Pfizer, Oxford-AstraZeneca and Moderna are fast-forwarding vaccine and therapeutics to treat Covid-19.

After intensive research, the scientists and doctors claim they have found 30 genes that block the virus from infecting human cells including RAB7A, a gene that seems to regulate theACE-2 receptorthat the virus binds to and uses to enter the cell. The spike proteins first contact with a human cell is through ACE-2 receptor.

Our findings confirmed what scientists believe to be true about ACE-2 receptors role in infection; it holds the key to unlocking the virus, said [virologist Dr. Benjamin] tenOever. It also revealed the virus needs a toolbox of components to infect human cells. Everything must be in alignment for the virus to enter human cells.

The research team also identified drugs that are currently on the market for different diseases that they claim block the entry ofCovid-19into human cells by increasing cellular cholesterol. In particular, they found three drugs currently on the market were more than 100-fold more effective in stopping viral entry in human lung cells.

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30+ genes identified that could protect us from COVID, opening door to gene therapy prevention solutions - Genetic Literacy Project

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