Category Archives: Genetic Medicine

The novel coronavirus causing COVID-19 seems to hit some people harder than others, with some people experiencing only mild symptoms and others being hospitalized and requiring ventilation. Though scientists at first thought age was the dominant factor, with young people avoiding the worst outcomes, new research has revealed a suite of features impacting disease severity. These influences could explain why some perfectly healthy 20-year-old with the disease is in dire straits, while an older 70-year-old dodges the need for critical interventions.

These risk factors include:AgeDiabetes (type 1 and type 2)Heart disease and hypertensionSmokingBlood typeObesityGenetic factors

About 8 out of 10 deaths associated with COVID-19 in the U.S. have occurred in adults ages 65 and older, according to the U.S. Centers for Disease Control and Prevention (CDC). The risk of dying from the infection, and the likelihood of requiring hospitalization or intensive medical care, increases significantly with age. For instance, adults ages 65-84 make up an estimated 4-11% of COVID-19 deaths in the U.S, while adults ages 85 and above make up 10-27%.

The trend may be due, in part, to the fact that many elderly people have chronic medical conditions, such as heart disease and diabetes, that can exacerbate the symptoms of COVID-19, according to the CDC. The ability of the immune system to fight off pathogens also declines with age, leaving elderly people vulnerable to severe viral infections, Stat News reported.

Related: Coronavirus in the US: Latest COVID-19 news and case counts

Diabetes mellitus a group of diseases that result in harmful high blood sugar levels also seems to be linked to risk of more severe COVID-19 infections.

The most common form in the U.S. is type 2 diabetes, which occurs when the body's cells don't respond to the hormone insulin. As a result, the sugar that would otherwise move from the bloodstream into cells to be used as energy just builds up in the bloodstream. (When the pancreas makes little to no insulin in the first place, the condition is called type 1 diabetes.)

In a review of 13 relevant studies, scientists found that people with diabetes were nearly 3.7 times more likely to have a critical case of COVID-19 or to die from the disease compared with COVID-19 patients without any underlying health conditions (including diabetes, hypertension, heart disease or respiratory disease), they reported online April 23 in the Journal of Infection.

Even so, scientists don't know whether diabetes is directly increasing severity or whether other health conditions that seem to tag along with diabetes, including cardiovascular and kidney conditions, are to blame.

That fits with what researchers have seen with other infections and diabetes. For instance, flu and pneumonia are more common and more serious in older individuals with type 2 diabetes, scientists reported online April 9 in the journal Diabetes Research and Clinical Practice. In a literature search of relevant studies looking at the link between COVID-19 and diabetes, the authors of that paper found a few possible mechanisms to explain why a person with diabetes might fare worse when infected with COVID-19. These mechanisms include: "Chronic inflammation, increased coagulation activity, immune response impairment and potential direct pancreatic damage by SARS-CoV-2."

Related: 13 coronavirus myths busted by science

Mounting research has shown the progression of type 2 diabetes is tied to changes in the body's immune system. This link could also play a role in poorer outcomes in a person with diabetes exposed to SARS-CoV-2, the virus that causes COVID-19.

No research has looked at this particular virus and immune response in patients with diabetes; however, in a study published in 2018 in the Journal of Diabetes Research, scientists found through a review of past research that patients with obesity or diabetes showed immune systems that were out of whack, with an impairment of white blood cells called Natural Killer (NK) cells and B cells, both of which help the body fight off infections. The research also showed that these patients had an increase in the production of inflammatory molecules called cytokines. When the immune system secretes too many cytokines,a so-called "cytokine storm" can erupt and damage the body's organs. Some research has suggested that cytokine storms may be responsible for causing serious complications in people with COVID-19, Live Science previously reported. Overall, type 2 diabetes has been linked with impairment of the very system in the body that helps to fight off infections like COVID-19 and could explain why a person with diabetes is at high risk for a severe infection.

Not all people with type 2 diabetes are at the same risk, though: A study published May 1 in the journal Cell Metabolism found that people with diabetes who keep their blood sugar levels in a tighter range were much less likely to have a severe disease course than those with more fluctuations in their blood sugar levels.

Scientists aren't sure whether this elevated risk of a severe COVID-19 infection also applies to people with type 1 diabetes (T1D). A study coordinated by T1D Exchange a nonprofit research organization focused on therapies for those with type 1 diabetes launched in April to study the outcomes of T1D patients infected with COVID-19. When a person with T1D gets an infection, their blood sugar levels tend to spike to dangerous levels and they can have a buildup of acid in the blood, something called diabetic ketoacidosis. As such, any infection can be dangerous for someone with type 1 diabetes.

People with conditions that affect the cardiovascular system, such as heart disease and hypertension, generally suffer worse complications from COVID-19 than those with no preexisting conditions, according to the American Heart Association. That said, historically healthy people can also suffer heart damage from the viral infection.

The first reported coronavirus death in the U.S., for instance, occurred when the virus somehow damaged a woman's heart muscle, eventually causing it to burst, Live Science reported. The 57-year-old maintained good health and exercised regularly before becoming infected, and she reportedly had a healthy heart of "normal size and weight." A study of COVID-19 patients in Wuhan, China, found that more than 1 in 5 patients developed heart damage some of the sampled patients had existing heart conditions, and some did not.

In seeing these patterns emerge, scientists developed several theories as to why COVID-19 might hurt both damaged hearts and healthy ones, according to a Live Science report.

In one scenario, by attacking the lungs directly, the virus might deplete the body's supply of oxygen to the point that the heart must work harder to pump oxygenated blood through the body. The virus might also attack the heart directly, as cardiac tissue contains angiotensin-converting enzyme 2 (ACE2) a molecule that the virus plugs into to infect cells. In some individuals, COVID-19 can also kickstart an overblown immune response known as a cytokine storm, wherein the body becomes severely inflamed and the heart could suffer damage as a result.

People who smoke cigarettes may be prone to severe COVID-19 infections, meaning they face a heightened risk of developing pneumonia, suffering organ damage and requiring breathing support. A study of more than 1,000 patients in China, published in the New England Journal of Medicine, illustrates this trend: 12.3% of current smokers included in the study were admitted to an ICU, were placed on a ventilator or died, as compared with 4.7% of nonsmokers.

Cigarette smoke might render the body vulnerable to the coronavirus in several ways, according to a recent Live Science report. At baseline, smokers may be vulnerable to catching viral infections because smoke exposure dampens the immune system over time, damages tissues of the respiratory tract and triggers chronic inflammation. Smoking is also associated with a multitude of medical conditions, such as emphysema and atherosclerosis, which could exacerbate the symptoms of COVID-19.

A recent study, posted March 31 to the preprint database bioRxiv, proposed a more speculative explanation as to why COVID-19 hits smokers harder. The preliminary research has not yet been peer-reviewed, but early interpretations of the data suggest that smoke exposure increases the number of ACE2 receptors in the lungs the receptor that SARS-CoV-2 plugs into to infect cells.

Many of the receptors appear on so-called goblet and club cells, which secrete a mucus-like fluid to protect respiratory tissues from pathogens, debris and toxins. It's well-established that these cells grow in number the longer a person smokes, but scientists don't know whether the subsequent boost in ACE2 receptors directly translates to worse COVID-19 symptoms. What's more, it's unknown whether high ACE2 levels are relatively unique to smokers, or common among people with chronic lung conditions.

Several early studies have suggested a link between obesity and more severe COVID-19 disease in people. One study, which analyzed a group of COVID-19 patients who were younger than the age of 60 in New York City, found that those who were obese were twice as likely as non-obese individuals to be hospitalized and were 1.8 times as likely to be admitted into critical care.

"This has important and practical implications" in a country like the U.S. where nearly 40% of adults are obese, the authors wrote in the study, which was accepted into the journal Clinical Infectious Diseases but not yet peer-reviewed or published. Similarly, another preliminary study that hasn't yet been peer-reviewed found that the two biggest risk factors for being hospitalized from the coronavirus are age and obesity. This study, published in medRxiv looked at data from thousands of COVID-19 patients in New York City, but studies from other cities around the world found similar results, as reported by The New York Times.

A preliminary study from Shenzhen, China, which also hasn't been peer-reviewed, found that obese COVID-19 patients were more than twice as likely to develop severe pneumonia as compared with patients who were normal weight, according to the report published as a preprint online in the journal The Lancet Infectious Diseases. Those who were overweight, but not obese, had an 86% higher risk of developing severe pneumonia than did people of "normal" weight, the authors reported. Another study, accepted into the journal Obesity and peer-reviewed, found that nearly half of 124 COVID-19 patients admitted to an intensive care unit in Lille, France, were obese.

It's not clear why obesity is linked to more hospitalizations and more severe COVID-19 disease, but there are several possibilities, the authors wrote in the study. Obesity is generally thought of as a risk factor for severe infection. For example, those who are obese had longer and more severe disease during the swine flu epidemic, the authors wrote. Obese patients might also have reduced lung capacity or increased inflammation in the body. A greater number of inflammatory molecules circulating in the body might cause harmful immune responses and lead to severe disease.

Blood type seems to be a predictor of how susceptible a person is to contracting SARS-CoV-2, though scientists haven't found a link between blood type per se and severity of disease.

Jiao Zhao, of The Southern University of Science and Technology, Shenzhen, and colleagues looked at blood types of 2,173 patients with COVID-19 in three hospitals in Wuhan, China, as well as blood types of more than 23,000 non-COVID-19 individuals in Wuhan and Shenzhen. They found that individuals with blood types in the A group (A-positive, A-negative and AB-positive, AB-negative) were at a higher risk of contracting the disease compared with non-A-group types. People with O blood types (O-negative and O-positive) had a lower risk of getting the infection compared with non-O blood types, the scientists wrote in the preprint database medRxiv on March 27; the study has yet to be reviewed by peers in the field.

In a more recent study of blood type and COVID-19, published online April 11 to medRxiv, scientists looked at 1,559 people tested for SARS-CoV-2 at New York Presbyterian hospital; of those, 682 tested positive. Individuals with A blood types (A-positive and A-negative) were 33% more likely to test positive than other blood types and both O-negative and O-positive blood types were less likely to test positive than other blood groups. (There's a 95% chance that the increase in risk ranges from 7% to 67% more likely.) Though only 68 individuals with an AB blood type were included, the results showed this group was also less likely than others to test positive for COVID-19.

The researchers considered associations between blood type and risk factors for COVID-19, including age, sex, whether a person was overweight, other underlying health conditions such as diabetes mellitus, hypertension, pulmonary diseases and cardiovascular diseases. Some of these factors are linked to blood type, they found, with a link between diabetes and B and A-negative blood types, between overweight status and O-positive blood groups, for instance, among others. When they accounted for these links, the researchers still found an association between blood type and COVID-19 susceptibility. When the researchers pooled their data with the research by Zhao and colleagues out of China, they found similar results as well as a significant drop in positive COVID-19 cases among blood type B individuals.

Why blood type might increase or decrease a person's risk of getting SARS-CoV-2 is not known. A person's blood type indicates what kind of certain antigens cover the surfaces of their blood cells; These antigens produce certain antibodies to help fight off a pathogen. Past research has suggested that at least in the SARS coronavirus (SARS-CoV), anti-A antibodies helped to inhibit the virus; that could be the same mechanism with SARS-CoV-2, helping blood group O individuals to keep out the virus, according to Zhao's team.

Many medical conditions can worsen the symptoms of COVID-19, but why do historically healthy people sometimes fall dangerously ill or die from the virus? Scientists suspect that certain genetic factors may leave some people especially susceptible to the disease, and many research groups aim to pinpoint exactly where those vulnerabilities lie in our genetic code.

In one scenario, the genes that instruct cells to build ACE2 receptors may differ between people who contract severe infections and those who hardly develop any symptoms at all, Science magazine reported. Alternatively, differences may lie in genes that help rally the immune system against invasive pathogens, according to a recent Live Science report.

For instance, a study published April 17 in the Journal of Virology suggests that specific combinations of human leukocyte antigen (HLA) genes, which train immune cells to recognize germs, may be protective against SARS-CoV-2, while other combinations leave the body open to attack. HLAs represent just one cog in our immune system machinery, though, so their relative influence over COVID-19 infection remains unclear. Additionally, the Journal of Virology study only used computer models to simulate HLA activity against the coronavirus; clinical and genetic data from COVID-19 patients would be needed to flesh out the role of HLAs in real-life immune responses.

Originally published on Live Science.

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Why COVID-19 kills some people and spares others. Here's what scientists are finding. - Livescience.com

A new study has sparked fears that the coronavirus has mutated to become more contagious, but experts say there is no evidence these changes make it any more dangerous or transmissible than it already is.

"Viruses mutate all the time, [and] most mutations have no significance even if they spread," said Adriana Heguy, director of the Genome Technology Center at New York University, who was not involved with the research.

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The study was posted on the preprint server bioRxiv on April 30. Preprints are studies that have not undergone the rigorous peer-review process required for publication in medical or scientific journals. In the rush to share new research on COVID-19, many scientists have been sharing their work online before undergoing the full review process.

The authors, who included researchers from the Los Alamos National Laboratory in New Mexico, analyzed the genetic sequences of samples of the virus gathered worldwide, zeroing in on a mutation called D614G.

"We were concerned that if the D614G mutation can increase transmissibility," the study authors wrote, "it might also impact severity of disease."

The corresponding author at the Los Alamos National Laboratory did not respond to an interview request from NBC News.

The hypothesis is concerning for a virus that has already infected millions and is responsible for more than 260,000 deaths worldwide.

But outside experts were quick to point out that changes in viruses especially coronaviruses are common, and may mean nothing at all.

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Dr. Gregory Poland, director of the Mayo Clinic's Vaccine Research Group in Rochester, Minnesota, explained viral mutations using the analogy of an automobile.

"If the mutation takes out your carburetor, the car can no longer operate," Poland said. "On the other hand, if the mutation changes one spark plug, the car can still operate."

What's unclear is whether the D614G mutation slows or speeds the viral "car" or, in fact, does nothing.

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Heguy said the D614G mutation had already been identified in viral sequences from around the globe, particularly in Europe.

The researchers "used that for their model to see if there was an indication that this particular mutation ... would make it more transmissible. According to their model, it is possible," Heguy said. "Having said that, it is only a model."

That is, models only reflect what could possibly happen in the future. Scientists have not found the virus has evolved to become any more dangerous or deadly in people.

Mutations are common in viruses, but the coronavirus "so far has been pretty darn stable with little mutations around the edges," Dr. William Schaffner, an infectious diseases expert at the Vanderbilt University Medical Center in Nashville, said.

"That's what these investigators are looking at," Schaffner said. "They're trying to determine whether these little mutations have implications for how well it's transmitted." But, there is "no evidence that this is happening that I can see clinically," he added.

Dr. Robert Gallo, the co-founder and director of the Institute of Human Virology at the University of Maryland School of Medicine, said "the paper, I believe, is a strong paper by a quality group."

But, he said, "no conclusions can be made about biology or functionality" of the virus based on this study.

While the research may not be reflective of any impact on patients, scientists say it's still incredibly useful as a way to track how the virus acts over time.

Poland noted that experts tracking the virus through its genetic sequencing have found that while it is changing, it's not doing so very quickly.

"Unlike influenza, this virus accumulates mutations more slowly, which is a good thing," he said. "It gives us time to track it and to understand what's happening."

Rapidly mutating viruses make it more difficult for researchers to develop vaccines. Flu vaccines, for example, are notoriously difficult to get right because the various strains of influenza have a tendency to change and mutate quickly.

If this virus were to follow suit, it might mean trouble for ongoing COVID-19 vaccine research.

"It's possible that you'll get vaccines early enough and quick enough to prevent [a person's] first infection with the coronavirus," Gallo said. "We may look like heroes that stop this early on."

But, if the virus mutates too much, and the vaccine proves to be a poor match to future strains of the coronavirus, "we may be chasing our tail like with influenza. And that's not a bright prospect with a virus that is already so infectious."

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Erika Edwards is a health and medical news writer and reporter for NBC News and "TODAY."

Tonya Bauer and Judy Silverman contributed.

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The coronavirus appears to have mutated. What does that mean for contagiousness? - NBC News

The coronavirus pandemic postponed Stephanie Goyas plan to finally defend her dissertation and complete her PhD in genomics. Like many scientists around the world, Goya, a virologist in Buenos Aires, quickly changed course to focus on the new coronavirus.

A lot of hands were needed, so with my expertise in viral genomics, I could help with different projects, said Goya, who works for Argentinas Dr. Ricardo Gutirrez Children's Hospital. I love it. I love to help society to bring expertise in something helpful, and this is the most helpful work I have ever done.

The pandemics deadly grip has sparked a global race to understand how the virus is evolving and spreading and the clues are in its genetic code. Goya is now part of a worldwide network of thousands of scientists trying to map and understand the genomic makeup of SARS-CoV-2, the scientific name for the new coronavirus, in near real time. Theyre drilling into the viruss structure to uncover clues about how it works, how it spreads, and ultimately, how it can be treated.

There is a lot to learn because this pathogen is new in humans. What excites Goya and other scientists is the unprecedented level of information scientists are sharing at a rapid pace. Its all possible through advances in genomic sequencing technology and improvements in the scientific culture of sharing.

Their work is helped along by online initiatives such as GISAID that facilitates the analysis and exchange of information. More than 20,000 people around the globe are registered to use its data.

Its a beginning of a new era.

Its a beginning of a new era, Goya said.

SARS-CoV-2 is complex. It contains a code of nearly 30,000 letters that represent the tiny structural units, or nucleotides, that make up the genome. Newer sequencing technology and algorithms have enabled the coding of virus samples in a matter of days and even hours, whereas in the past it would have taken weeks.

Scientists have used full genomic sequencing to understand and respond to other outbreaks, most recently Ebola. But never before has it been used at this speed and scale.

Critical to comprehending the nature of this virus is scientists willingness and ability to share information from the start, as opposed to delaying the release of data until the full publication of its analysis, which can take months or years.

Related: COVID-19: The latest from The World

One of Africas leading scientists, Christian Happi, is heading the effort to map the genome of the new coronavirus across the continent. He directs the African Center of Excellence for Genomics of Infectious Diseases at Redeemers University in Nigeria and had helped sequence the Ebola genome then used sequencing technology to track its spread. In February, Happi got a sample of SARS-CoV-2 from a patient in his lab in Ede. He immediately got to work and shared the results.

We had the whole genome of the virus lined up, the whole genetic map. That was unprecedented because we were able to do it in 48 hours.

We had the whole genome of the virus lined up, the whole genetic map, Happi said. That was unprecedented because we were able to do it in 48 hours.

Halfway across the world in New York City, geneticist Harm van Bakel has been racing to map the new coronavirus, too. The lab he runs at the Icahn School of Medicine at Mount Sinai is collecting samples from infected patients across New York City and countries that dont yet have the lab capacity.

Given the number of samples were currently processing, we sequence maybe 100 viruses every two to three days, van Bakel said.

Van Bakel normally studies the spread of other pathogens such as seasonal influenza. He stressed that the speed at which researchers are able to sequence and understand so many samples of the new coronavirus allows them to track its transmission. Thats because as the virus spreads, it accumulates small changes in its genetic code, van Bakel said.

These changes occur because when a virus infects someone new, it makes lots of copies, creating new virus particles. The machinery that does this isnt perfect. It can make small mistakes as it replicates. Those mistakes or mutations give each virus its own unique tag, like a scratch on a car.

It doesnt necessarily impact how the car functions, but it allows you to differentiate one particular car from a different car of the same type, van Bakel said.

Related: Studies on whales, cosmos among research derailed by pandemic

These scratches help scientists identify the path of this virus, while also tracking whether any of those changes impact the viruss behavior, which scientists continue to monitor.

When pieced together through this global sharing of sequencing information, Happi has been able to see how the virus spread to Nigeria from China. Van Bakel was able to glean that the virus in New York appeared very similar to the one that was circulating in Europe.

And what that tells us in return is that as the virus spread from Asia, it didnt come directly to New York but rather, it took a detour through Europe.

And what that tells us in return is that as the virus spread from Asia, it didnt come directly to New York but rather, it took a detour through Europe, van Bakelsaid.

Data generated by scientists like Happi and van Bakel is helping other researchers understand where variations of the coronavirus have spread around the world. That piece of the puzzle could help policymakers respond to new outbreaks.

Emma Hodcroft, a molecular epidemiologist at the University of Basel in Switzerland and Nextstrain, has been downloading that data to create a kind of global map of the virus called a phylogenetic tree.

The branches represent evolutionary relationships of the virus. The whole map currently includes more than 10,000 sequences of the new coronavirus.

So, if we can find out what were the dangers beforehand, how did this virus spread effectively between different states or between different cities, we can keep an eye on that as we come out of lockdown to make sure that we don't give the virus that advantage when we try and start re-allowing movement and reopening shops and this kind of thing, Hodcroft said.

Being able to source and analyze all this data is no small feat: It requires a credible system for sharing this information and scientists who are willing to participate. Several platforms now exist such as Genbank, EMBL-EBI, and a global consortium, the International Nucleotide Sequence Database Collaboration. One of the main public-private initiatives that Hodcroft and others take part in is GISAID, the nonprofit Global Initiative on Sharing All Influenza Data.

With scientific advisers across the world, GISAID was already a well-oiled system when the coronavirus hit.

It's an exponential growth that is staggering.

We were called earlier this year, the first week of January, by our partners in China and various public health laboratories to see if we could assist with the sharing of a newly emerging coronavirus, said GISAIDs founder, Peter Bogner. It's an exponential growth that is staggering.

Anyone can access GISAID, so long as they register and agree to credit the scientist whose data in any resulting research. Bogner said those conditions helped relieve tension among scientists who may have been reluctant to share data prepublication because they were worried about being scooped.

The initiative has existed since 2008. It emerged from a system of labs around the world that track and share genetic data for flu viruses. GISAID is a critical source for identifying strains for developing annual flu vaccines.

Global health hinges on this kind of collaboration. But there are major gaps: Not all countries have the capacity to collect and sequence the new coronavirus, which leads to blind spots in tracing it.

For example, it wasnt until late April that researchers in Argentina had the necessary ingredients to sequence and share the first genomes of the virus there, said Goya, the Buenos Aires virologist. Bogner said GISAID is working with scientists in Tehran, to help the country begin sequencing the genome and sharing it.

For Happi, the scientist in Nigeria, another question looms: Who benefits when these sequences lead to an effective vaccine or treatment?

The companies that are developing tools and diagnostics and vaccines should understand that because we shared the data that we should share in terms of the benefit, he said.

Happi worries that communities vital to effort may not have equal access to lifesaving treatment once genomic data is used to successfully develop it. Or that the treatment might be too expensive. Scientists and policymakers havent solved that problemat least, not yet.

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Inside the global network of scientists racing to curb the spread of coronavirus - The World

A group of researchers from the University of Toronto and the Hospital for Sick Childrenhave developed a new wayto deliver molecules that target specific genes within cells. The platform, which uses a modified form of diphtheria toxin, has been shown to downregulate critical genes in cancer cells, and could be used for other genetic diseases as well.

The team, led by University ProfessorMolly Shoichet of the Faculty of Applied Science & Engineeringand Roman Melnyk, anassociateprofessorthe department of biochemistry in the Faculty of Medicine and a senior scientist at SickKids, found inspiration from an unexpected source: diphtheria toxin.

The research was published recently in the journal Science Advances.

Scientists looking to place molecules inside cells have a number of existing tools to choose from, but most suffer from the same drawback: while the molecule gets inside the cell, it remains trapped in a kind of bubble called an endosome. If the goal is to deliver therapeutics that will interact with the cells DNA, breaking out of the endosome is critical.

As a natural defence mechanism, bacteria such as Corynebacterium diphtheriae producea protein-based toxin that enters surrounding cells, eventually killing them. Critically, this toxin is known to be capable of escaping from endosomes, which led to the idea of re-engineering it as a delivery platform.

Melnyks lab specializes in bacterial toxins and invented a non-toxic version of the diphtheria toxin, known as attenuated diphtheria toxin. This new molecule has the capacity to enter the cell and efficiently escape the endosome and thus excels as a delivery vehicle without any of the toxic effects of diphtheria toxin.

To prove that the concept would work, the researchers used the system to deliver molecules that they believed would be effective against glioblastoma, a form of brain cancer.

Glioblastoma is a highly invasive disease and patients have a very short life expectancy after initial diagnosis, says Shoichet. We want to change this and have thus pursued the delivery of gene therapeutics to treat glioblastoma.

The group first targeted glioblastoma neural stem cells, which are thought to be resistant to chemotherapeutics. Specifically, the researchers focused on delivering silencing RNA (siRNA) against two genes: integrin beta 1 (ITGB1), which is associated with the highly invasive nature of glioblastoma (and other cancers), and eukaryotic translation initiation factor 3 sub-unit b (eIF-3b), which is an essential survival gene. By eliminating this invasive trait, the researchers could potentially limit progression in diseases like cancer.

ITGB1 is involved in cancer cell migration, which contributes to glioblastomas invasion into healthy brain tissues, saysLaura Smith, a senior PhD student on the publication. We used an innovative three-dimensional culture system to significantly reduce cell invasion after treatment with our siRNA-attenuated diphtheria toxin system, which suggests that it may be effective in slowing disease progression.

To demonstrate the breadth of this platform, the researchers also delivered a different nucleic sequence that knocks down eIF-3b, which participates in the survival pathway of cancer cells.

We treated the cells with the attenuated diphtheria toxin-siRNA against eIF-3b and observed downregulation at genetic and phenotypic levels, saysAmy E. Arnold, a recent PhD graduate from the Shoichet lab and first author on the paper.

The group is planning on using this delivery vehicle to treat other diseases in the future.

We recognize the strength of this platform strategy and are actively testing it for the delivery of RNA and other cargoes, Shoichet says.

The research received support from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada, among others.

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U of T researchers use diphtheria toxin to target genes in cancer cells - News@UofT

With the FDA approving Gileads Remdesivir as an emergency use treatment for the most acute cases of COVID-19, many people are wondering what type of a drug it is.

Remdesivir is a member of one of the oldest and most important classes of drugs known as nucleoside analogue. Currently there are more than 30 of these types of drugs that have been approved for use in treating viruses, cancers, parasites, as well as bacterial and fungal infections, with many more currently in clinical and preclinical trials.

I am a medicinal chemist who has worked in design and synthesis of these important drug treatments for over 30 years. I have written numerous reviews over the years about these drugs and their structure and function, and as a result have had many inquiries lately from friends, family and others not in the field asking me to explain what exactly is it about Remdesivir that makes it so effective, but also why it is so interesting. Understanding why means digging into the biochemistry of this class of drugs.

The reason nucleoside analogues and a similar group called nucleotide analogues are so effective is that they resemble the naturally occurring molecules known as nucleosides cytidine, thymidine, uridine, guanosine and adenosine. These are the essential building blocks for the DNA and RNA that carry our genetic information and play critical roles in our bodys biological processes.

Slight differences in the chemical structure of these analogues from naturally occurring compounds make them effective as drugs. If an organism like a virus incorporates a nucleoside analogue into its genetic material, rather than the real thing, even small changes to the structure of these building blocks prevent the regular chemistry from happening and ultimately foils the ability of the virus to replicate.

The basic structure of a nucleoside includes a sugar group and a base (A, C, G, T or U), and in the case of a nucleotide, a group containing a phosphate which is a collection of oxygen and phosphorus atoms.

The first nucleoside analogues were approved for medicinal use in the 1950s. The early nucleosides had only simple modifications, typically either to the sugar or the base, while todays nucleosides, such as Remdesivir, typically have several modifications to their structure. These modifications are essential to their therapeutic activity.

This activity occurs because nucleoside/tide analogues mimic the structure of a natural nucleoside or nucleotide such that they are recognized by, for example, viruses. Due to those structural modifications, however, they stop or interrupt viral replication, which stops the virus from multiplying and infecting more cells in the body.

As a result, they are known as direct-acting antivirals, and this is the case for Remdesivir, which works by blocking the coronaviruss RNA polymerase one of the key enzymes that this virus needs to replicate its genetic material (RNA) and proliferate in our bodies. Remdesivir works when the enzyme replicating the genetic material for a new generation of viruses accidentally grabs this nucleoside analogue rather than the natural molecule and incorporates it into the growing RNA strand. Doing this essentially blocks the rest of the RNA from being replicated; this in turn prevents the virus from multiplying.

The drug Remdesivir is basically an altered version of the natural building block adenosine which is essential for DNA and RNA. Comparing the structure of Remdesivir with adenosine, one can see there are three key modifications that make it effective.

The first is that Remdesivir, as it is administered, is not the actual active drug; it is actually a prodrug, meaning it must be modified once in the body before it becomes an active drug. Prodrugs are used for many reasons, including protecting a drug until it reaches its site of action. The active form of Remdesivir contains three phosphate groups; it is this form that is recognized by the viruss RNA polymerase enzyme.

The second important modification on Remdesivir is the carbon-nitrogen (CN) group attached to the sugar. Once Remdesivir is incorporated into the RNA growing chain, the presence of this CN group causes the shape of the sugar to pucker, which, in turn, distorts the shape of the RNA strand such that only three more nucleotides can be added. This terminates the production of the RNA strand and is what ultimately sabotages the replication of the virus.

The third important structural feature which makes Remdesivir differ from adenosine is the change of one particular chemical bond on the molecule. Rather than a bond linking a carbon and nitrogen atoms, chemists replaced the nitrogen with another carbon, creating a carbon-carbon bond. This is critical to the success of this drug because coronaviruses have a special enzyme that recognizes unnatural nucleosides and clips them out. But by changing this chemical bond, Remdesivir cannot be removed by the enzyme, allowing it to stay in the growing chain and block replication.

Remdesivir originally was found during a drug discovery program at Gilead to search for inhibitors of the hepatitis C virus, which is another RNA virus. Although Gilead ultimately selected a different nucleoside analogue for treatment of hepatitis the company tested the drug to see if it was effective against other RNA viruses. Remdesivir exhibited potent activity against Ebola and Middle Eastern respiratory virus, among others.

Now the drug is being tested against the SAR-CoV-2 virus in the first clinical trial launched in the United States.

According to the NIH, patients who received Remdesivir had a faster recovery compared to those who received placebo; 11 days compared with 15 days for those who received the placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving Remdesivir versus 11.6% for the placebo group, according to the NIH press release.

While these results are preliminary, there are a plethora of clinical trials underway across the world. Regardless, a certain amount of caution is still needed. As noted by Dr. Anthony Fauci on NBCs Today show, the antiviral drug Remdesivir is the first step in what we project will be better and better drugs coming along to treat COVID-19, but cautioned, This is not the total answer.

I share this view with many other scientists in the field. No matter what those results ultimately show, Remdesivir will mostly certainly be part of a cocktail of drugs, just as is standard for treating other viruses such as HIV and hepatitis C.

A combination, or cocktail, of drugs will provide a more effective and more complete therapy that blocks the virus from replicating. The other benefit of such a drug cocktail is that it lowers the chance the virus will develop resistance to the therapy. In the meantime, these early results for Remdesivir are proving to be an important source of hope for many of us across the world as we wait for this pandemic to subside.

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Remdesivir explained what makes this drug work against viruses? - The Conversation US

Snow Medical founder Terry Snow said: COVID-19 has had a devastating effect on Australia and the world this is the biggest thing to hit the globe since 1945 and it will have a lasting impact for years to come. Government has stepped up and now is the time for the community to play a role. All these measures are aimed at getting Australians back to work, making treatment more effective and efficient getting our economy working again.

Snow Medical chair, Tom Snow, added: We want to help Australias best and brightest to focus their efforts on this huge national and global challenge.

This consortium is particularly notable because of its national reach and collaborative networks it draws on research expertise from over 15 Universities and Medical Research institutes, their affiliated public hospitals, State Health Departments, public health authorities, pathology services and the Australian Red Cross Blood Service to provide a truly national picture and coordinated approach to beating COVID-19.

Professor Tania Sorrell who is director of the University of Sydneys Marie Bashir Institute for Infectious Diseases and Biosecurity, Infectious Diseases Group head in The Westmead Institute of Medical Research and the lead investigator in CREID said: This very generous donation will help Australia lead in the fight to contain spread of COVID-19 in the community, better protect health care workers, and offer the best care to individual patients.

Critically, the vision of Snow Medical has enabled CREID and APPRISE to leverage the joint power of their national research networks in the fight against COVID-19.

Professor Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity (Doherty Institute), a joint venture of the University of Melbourne and The Royal Melbourne Hospital, and chief investigator for APPRISE said: The large injection of funds supports the development of critical national platforms for the current pandemic while building capacity for future pandemics."

Infectious diseases physician and trials expert at the University of Sydneys Faculty of Medicine and Health, Professor Tom Snelling, who will be leading the data science project, said: Australias brisk and effective response to COVID-19 is the envy of many countries but we cant afford to become complacent. This donation will give researchers a critical boost in their race to find and implement science-driven solutions for the pandemic.

Link:
New medical foundation invests in COVID-19 research funding - News - The University of Sydney