Gene consultants declare they’ve recognized human genes that may defend towards Covid-19

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 the Icahn School of Medicine at Mount Sinai said they had identified the genes that can protect human cells from Covid-19, a disease that affects over 40 million Infected people and which resulted in 1 million deaths worldwide.

The discovery comes after eight months of screening all 20,000 genes in the human genome under the direction of Dr. Neville Sanjana at the New York Genome Center. The leading virologist on Mount Sinai, Dr. Benjamin tenOever, developed a set of human lung cell models for coronavirus screening to better understand immune responses to the disease, and co-authored the study.

Their study, published online by Cell last month, will appear in the January 7 print edition of the journal.

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

The breakthrough comes at a time when drug makers like Pfizer, Oxford-AstraZeneca, and Moderna are rapidly advancing vaccines and therapeutics to treat Covid-19. On Friday, Pfizer and BioNTech filed with the FDA for emergency approval for their Covid vaccine, which contains genetic material called messenger RNA. Scientists expect the immune system to fight the virus.

To better understand the complex relationships between host and virus genetic dependencies, the team used a wide range of analytical and experimental methods to validate their results. This integrative approach included genome editing, individual cell sequencing, confocal imaging, and computational analysis of gene expression and proteomic data sets.

After extensive research, the scientists and doctors claim to have found 30 genes that prevent the virus from infecting human cells, including RAB7A, a gene that appears to regulate the ACE-2 receptor to which the virus binds and which it used to invade the cell. The first contact of the spike protein with a human cell occurs via the ACE-2 receptor.

"Our results confirmed what scientists believe to be true about the role of the ACE-2 receptor in infection. It is key to the release of the virus," said Dr. tenOever. "It also found that the virus needs a toolbox of components to infect human cells. Everything has to be in line for the virus to enter human cells."

The team discovered that the high-level genes – those whose loss greatly reduces viral infection – clustered together into a handful of protein complexes, including Vacuolar ATPases, Retromer, Commander, Arp2 / 3, and PI3K. Many of these protein complexes are involved in the transport of proteins to and from the cell membrane.

"We were delighted to see multiple genes within the same family as top hits in our genome-wide screening. This gave us a high level of confidence that these protein families were critical to the virus life cycle, either to get into human cells or to successful virus replication "said Dr. Zharko Daniloski, postdoctoral fellow at the Sanjana Lab and co-first author of the study.

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

Cholesterol and the virus

The research team also identified drugs currently on the market for various diseases that they claim block the entry of Covid-19 into human cells by increasing cellular cholesterol. Specifically, they found that three drugs currently on the market were more than 100 times more effective at stopping the virus from entering human lung cells:

  • Amlodipine, Brand name Norvasc from Pfizer, used to treat high blood pressure and angina.
  • Tamoxifen, Brand name Soltamox of Fortovia Therapeutics, an estrogen modulator used in the treatment of breast cancer.
  • Ilomastat, Brand name Galardin, is a matrix metalloprotease inhibitor that is now manufactured by many companies. a chemotherapy drug with uses in skin care and antiaging products.

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

Our results confirmed what scientists believe to be true about the role of the ACE-2 receptor in infection. It contains the key to unlock the virus.

Their results provide insights into novel therapies that may be effective in treating Covid-19 and reveal the underlying molecular goals of these therapies.

The New York bioengineers were working on other projects using CRISPR's gene editing technology, but quickly turned to studying the coronavirus as it swept the metropolitan area in March last year. "Given the tragic impact of Covid-19 here in New York and around the world, we felt we could use the high throughput CRISPR gene editing tools that we have used on other diseases to understand what key human genes are needed by the world. " 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 from Covid-19.

New York Genome Center

As he explained, "Current treatments for SARS-CoV-2 infection currently trace back to the virus itself, but this study provides a better understanding of how host genes affect virus entry and will enable new avenues for therapeutic discovery."

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

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

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

The potential of using CRISPR to eradicate viruses has already generated some excitement in the research community. Last year, for example, Excision BioTherapeutics licensed Temple University technology that uses CRISPR in combination with antiretroviral therapy to eliminate HIV, the virus that causes AIDS.

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