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RNA Therapies Small Beginnings to Big Opportunities

By Scott Ripley, PhD, and Tracy Humphries Scientists have always dreamed big. Before the COVID-19 pandemic, investigators working on RNA therapeutics were…

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By Scott Ripley, PhD, and Tracy Humphries

Scott Ripley, PhD
Cytiva

Scientists have always dreamed big. Before the COVID-19 pandemic, investigators working on RNA therapeutics were able to envisage its potential and impact on the field of medicine. The success of mRNA-based COVID-19 vaccines accelerated the market for RNA-based medicines and enabled manufacturers to gain traction.

mRNA-based therapies gained popularity for several reasons:

  • mRNA is a versatile molecule that can be easily synthesized and modified.
  • mRNA-based therapies are considered safe and are used in COVID-19 vaccines.
  • mRNA-based therapies have the potential to treat a wide range of diseases.

RNA can target specific cells, encode proteins, and trigger immune responses, enabling its use in vaccines and cell and gene therapies. However, the development of mRNA-based vaccines and therapies can still face challenges, such as targeted delivery, efficacy, stability, and scalability.

Tracy Humphries
Tracy Humphries
Cytiva

Nevertheless, the potential of mRNA therapeutics is significant. Their rise has been exponential, and the number of therapies in clinical trials continues to increase. mRNA-based therapies show promise for the treatment of cancer, genetic disorders, and infectious diseases.

The technology that the coronavirus vaccine is built upon is now widely known. Moderna and BioNTech were at the forefront of mRNA technology, with their COVID-19 vaccines being the first to receive emergency use authorization.

mRNA vaccines, which deliver genetic instructions to cells to make a specific protein to trigger an immune response, are highly adaptable and can be quickly designed and manufactured to target new pathogens. Further vaccines are in development, not only for COVID-19, but for other infectious diseases such as influenza, Zika virus, cytomegalovirus, and respiratory syncytial virus. Companies working on such vaccines include Moderna, Pfizer, BioNTech, CureVac, and Sanofi.

mRNAs to form CAR proteins

An exciting branch of RNA therapeutics is mRNA-based immunotherapy. It involves the delivery of chimeric antigen receptor (CAR)-encoding mRNA to T cells. Essentially, the approach uses mRNA to reprogram T cells so that they target and kill cancer cells. It has the potential to treat a wide range of cancers, including leukemia and lymphoma.

The production of CAR T cells in vivo has been demonstrated to treat cardiac injury by delivering modified mRNA in T-cell-targeted lipid nanoparticles. Conventional CAR T-cell therapies have high manufacturing costs due to the infrastructure and reagents needed. Lipid nanoparticle–based mRNA therapy negates the need to expand T cells outside the body and can be a more cost-effective method.

Combinatorial therapies are also promising, as BioNTech has shown with BNT211, which is a synergistic approach combining the company’s CAR T-cell and FixVac platform technologies to develop a highly tumor-specific CAR T-cell therapy product, which is enhanced by a CAR T-cell amplifying RNA vaccine (CARVac).

mRNA manufacturing dedicated equipment
In mRNA manufacturing, appropriate strategies—and dedicated equipment and consumables—are needed at every stage. These stages include plasmid linearization, in vitro transcription, buffer exchange, capture (mRNA purification), concentration (volume reduction and change to stable salt conditions), lipid nanoparticle formation, polishing, and final packaging.

mRNA as a cancer vaccine

The success of the mRNA-based COVID-19 vaccines owes much to the research that was originally focused on cancer vaccines. To accelerate the development of the Pfizer/BioNTech and Moderna COVID-19 vaccines, all the companies leveraged their cancer vaccine experience. There are many clinical trials in progress for mRNA vaccine treatment of melanoma and colorectal and pancreatic cancer.

mRNA cancer vaccines can work with a one-vaccine-to-many-people approach, or as a personalized therapy. Dendritic cells take up mRNA from the vaccine and present it to T cells, teaching them to search out and destroy cancer cells.

Personalized vaccines are manufactured based on molecular features of tumors from individuals to identify genetic mutations that could give rise to neoantigens. Algorithms are used to predict which neoantigens will bind to T-cell receptors and create an immune response. Speed of manufacturing is particularly important in this case, which is one of the reasons that mRNA is a suitable modality.

Companies working in this space include eTheRNA, Moderna, BioNTech, Merck & Co., and Genentech.

Gene therapy protein replacement

Protein replacement therapies address protein deficiencies, raising protein levels that are too low, or substituting functional for nonfunctional proteins. mRNA can be used to produce therapeutic proteins within the body—for example, by instructing cells to produce a specific protein that corrects a disease-causing genetic effect. In cystic fibrosis, mRNA can encode a functional copy of the cystic fibrosis transmembrane conductance regulator protein, which is deficient in patients, an approach used by Vertex Pharmaceuticals and Moderna. Likewise, Arcturus Therapeutics has presented data establishing proof of principle of a novel mRNA replacement therapy to treat phenylketonuria.

RNA therapeutics may have an advantage over more invasive and permanent gene editing procedures. mRNA protein replacement therapies will, however, require much larger doses than traditional vaccines. Other RNA modalities, such as circular RNA (circRNA) and self-amplifying RNA (saRNA), allow for lower mRNA requirements per dose.

Gene editing approach

mRNA can deliver gene editing tools such as CRISPR-Cas9 to cells and tissues, making it possible for the tools to correct deleterious mutations that cause genetic disorders. For example, mRNA-delivered gene editing tools can correct mutations in the HBB gene that lead to sickle-cell disease. Similarly, mRNA-delivered gene editing tools can eliminate aberrant splicing sites that cause b-thalassemia. mRNA can also deliver gene editing tools to cancer cells, enabling precise genomic modifications that make the cells more vulnerable to immune attack.

When gene therapies are delivered by mRNA, “one dose and done” treatments are possible. In contrast, mRNA therapies that rely on mRNA to express therapeutic proteins typically involve repeat doses.

At GreenLight Biosciences, mRNA delivery technology is part of the company’s strategy to develop an in vivo gene therapy for sickle-cell disease. The company is also assessing treatments for HIV. Besides GreenLight, companies in this space include Editas Medicine, Beam Therapeutics, CRISPR Therapeutics, and Intellia Therapeutics.

Cytiva scientist
For mRNA technology to realize its enormous potential in vaccines and therapeutics, practical challenges such as targeted delivery, efficacy, stability, and scalability will need to be overcome. Fortunately, tools and technologies are available to assist process development and manufacturing efforts. For example, there are solutions for plasmid selection, downstream purification, lipid nanoparticle analysis, and aseptic filling.

CircRNAs for apoptosis and aging

CircRNAs are noncoding closed RNAs that appear to work in conjunction with microRNAs. Several circRNAs have been found to enhance or inhibit tumor progression in various types of human cancer. They have also been found to be involved in adipose metabolism. In addition, they are believed to influence aging, to function in multiple disorders, to regulate gene expression, and to modulate programmed cell death pathways such as apoptosis pathways.

As circRNAs are stable and expressed in a tissue type– or cell type–specific manner, they are also being explored as therapeutic targets. Expanding our knowledge of circRNA functional mechanisms and approaches to target in vivo will be key to unlocking circ-based therapeutics.

Several RNA therapeutic approaches have been mentioned in this article. In general, each approach has been treated singularly. However, there are many ways these approaches may be merged, resulting in combinatorial therapies. In addition, the RNA therapeutic approaches described here may be combined with other modalities not mentioned in this article.

There is a lot of potential for RNA therapeutics, especially since they facilitate a toolbox approach to treatment modalities. For a given target, the right modality or modalities can be selected, with RNA therapies augmenting or serving as alternatives to more traditional approaches. By offering compatibility or disruptiveness, as needed, RNA therapies also support more innovative thinking. Ultimately, they promise to expand the genomic medicine universe.

 

Scott Ripley, PhD, is general manager and Tracy Humphries is marketing leader of the nucleic acid therapeutics business at Cytiva.

 

The post RNA Therapies Small Beginnings to Big Opportunities appeared first on GEN - Genetic Engineering and Biotechnology News.

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Are Voters Recoiling Against Disorder?

Are Voters Recoiling Against Disorder?

Authored by Michael Barone via The Epoch Times (emphasis ours),

The headlines coming out of the Super…

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Are Voters Recoiling Against Disorder?

Authored by Michael Barone via The Epoch Times (emphasis ours),

The headlines coming out of the Super Tuesday primaries have got it right. Barring cataclysmic changes, Donald Trump and Joe Biden will be the Republican and Democratic nominees for president in 2024.

(Left) President Joe Biden delivers remarks on canceling student debt at Culver City Julian Dixon Library in Culver City, Calif., on Feb. 21, 2024. (Right) Republican presidential candidate and former U.S. President Donald Trump stands on stage during a campaign event at Big League Dreams Las Vegas in Las Vegas, Nev., on Jan. 27, 2024. (Mario Tama/Getty Images; David Becker/Getty Images)

With Nikki Haley’s withdrawal, there will be no more significantly contested primaries or caucuses—the earliest both parties’ races have been over since something like the current primary-dominated system was put in place in 1972.

The primary results have spotlighted some of both nominees’ weaknesses.

Donald Trump lost high-income, high-educated constituencies, including the entire metro area—aka the Swamp. Many but by no means all Haley votes there were cast by Biden Democrats. Mr. Trump can’t afford to lose too many of the others in target states like Pennsylvania and Michigan.

Majorities and large minorities of voters in overwhelmingly Latino counties in Texas’s Rio Grande Valley and some in Houston voted against Joe Biden, and even more against Senate nominee Rep. Colin Allred (D-Texas).

Returns from Hispanic precincts in New Hampshire and Massachusetts show the same thing. Mr. Biden can’t afford to lose too many Latino votes in target states like Arizona and Georgia.

When Mr. Trump rode down that escalator in 2015, commentators assumed he’d repel Latinos. Instead, Latino voters nationally, and especially the closest eyewitnesses of Biden’s open-border policy, have been trending heavily Republican.

High-income liberal Democrats may sport lawn signs proclaiming, “In this house, we believe ... no human is illegal.” The logical consequence of that belief is an open border. But modest-income folks in border counties know that flows of illegal immigrants result in disorder, disease, and crime.

There is plenty of impatience with increased disorder in election returns below the presidential level. Consider Los Angeles County, America’s largest county, with nearly 10 million people, more people than 40 of the 50 states. It voted 71 percent for Mr. Biden in 2020.

Current returns show county District Attorney George Gascon winning only 21 percent of the vote in the nonpartisan primary. He’ll apparently face Republican Nathan Hochman, a critic of his liberal policies, in November.

Gascon, elected after the May 2020 death of counterfeit-passing suspect George Floyd in Minneapolis, is one of many county prosecutors supported by billionaire George Soros. His policies include not charging juveniles as adults, not seeking higher penalties for gang membership or use of firearms, and bringing fewer misdemeanor cases.

The predictable result has been increased car thefts, burglaries, and personal robberies. Some 120 assistant district attorneys have left the office, and there’s a backlog of 10,000 unprosecuted cases.

More than a dozen other Soros-backed and similarly liberal prosecutors have faced strong opposition or have left office.

St. Louis prosecutor Kim Gardner resigned last May amid lawsuits seeking her removal, Milwaukee’s John Chisholm retired in January, and Baltimore’s Marilyn Mosby was defeated in July 2022 and convicted of perjury in September 2023. Last November, Loudoun County, Virginia, voters (62 percent Biden) ousted liberal Buta Biberaj, who declined to prosecute a transgender student for assault, and in June 2022 voters in San Francisco (85 percent Biden) recalled famed radical Chesa Boudin.

Similarly, this Tuesday, voters in San Francisco passed ballot measures strengthening police powers and requiring treatment of drug-addicted welfare recipients.

In retrospect, it appears the Floyd video, appearing after three months of COVID-19 confinement, sparked a frenzied, even crazed reaction, especially among the highly educated and articulate. One fatal incident was seen as proof that America’s “systemic racism” was worse than ever and that police forces should be defunded and perhaps abolished.

2020 was “the year America went crazy,” I wrote in January 2021, a year in which police funding was actually cut by Democrats in New York, Los Angeles, San Francisco, Seattle, and Denver. A year in which young New York Times (NYT) staffers claimed they were endangered by the publication of Sen. Tom Cotton’s (R-Ark.) opinion article advocating calling in military forces if necessary to stop rioting, as had been done in Detroit in 1967 and Los Angeles in 1992. A craven NYT publisher even fired the editorial page editor for running the article.

Evidence of visible and tangible discontent with increasing violence and its consequences—barren and locked shelves in Manhattan chain drugstores, skyrocketing carjackings in Washington, D.C.—is as unmistakable in polls and election results as it is in daily life in large metropolitan areas. Maybe 2024 will turn out to be the year even liberal America stopped acting crazy.

Chaos and disorder work against incumbents, as they did in 1968 when Democrats saw their party’s popular vote fall from 61 percent to 43 percent.

Views expressed in this article are opinions of the author and do not necessarily reflect the views of The Epoch Times or ZeroHedge.

Tyler Durden Sat, 03/09/2024 - 23:20

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Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Authored by Zachary Stieber via The Epoch Times (emphasis ours),

The…

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Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Authored by Zachary Stieber via The Epoch Times (emphasis ours),

The U.S. Department of Veterans Affairs (VA) reviewed no data when deciding in 2023 to keep its COVID-19 vaccine mandate in place.

Doses of a COVID-19 vaccine in Washington in a file image. (Jacquelyn Martin/Pool/AFP via Getty Images)

VA Secretary Denis McDonough said on May 1, 2023, that the end of many other federal mandates “will not impact current policies at the Department of Veterans Affairs.”

He said the mandate was remaining for VA health care personnel “to ensure the safety of veterans and our colleagues.”

Mr. McDonough did not cite any studies or other data. A VA spokesperson declined to provide any data that was reviewed when deciding not to rescind the mandate. The Epoch Times submitted a Freedom of Information Act for “all documents outlining which data was relied upon when establishing the mandate when deciding to keep the mandate in place.”

The agency searched for such data and did not find any.

The VA does not even attempt to justify its policies with science, because it can’t,” Leslie Manookian, president and founder of the Health Freedom Defense Fund, told The Epoch Times.

“The VA just trusts that the process and cost of challenging its unfounded policies is so onerous, most people are dissuaded from even trying,” she added.

The VA’s mandate remains in place to this day.

The VA’s website claims that vaccines “help protect you from getting severe illness” and “offer good protection against most COVID-19 variants,” pointing in part to observational data from the U.S. Centers for Disease Control and Prevention (CDC) that estimate the vaccines provide poor protection against symptomatic infection and transient shielding against hospitalization.

There have also been increasing concerns among outside scientists about confirmed side effects like heart inflammation—the VA hid a safety signal it detected for the inflammation—and possible side effects such as tinnitus, which shift the benefit-risk calculus.

President Joe Biden imposed a slate of COVID-19 vaccine mandates in 2021. The VA was the first federal agency to implement a mandate.

President Biden rescinded the mandates in May 2023, citing a drop in COVID-19 cases and hospitalizations. His administration maintains the choice to require vaccines was the right one and saved lives.

“Our administration’s vaccination requirements helped ensure the safety of workers in critical workforces including those in the healthcare and education sectors, protecting themselves and the populations they serve, and strengthening their ability to provide services without disruptions to operations,” the White House said.

Some experts said requiring vaccination meant many younger people were forced to get a vaccine despite the risks potentially outweighing the benefits, leaving fewer doses for older adults.

By mandating the vaccines to younger people and those with natural immunity from having had COVID, older people in the U.S. and other countries did not have access to them, and many people might have died because of that,” Martin Kulldorff, a professor of medicine on leave from Harvard Medical School, told The Epoch Times previously.

The VA was one of just a handful of agencies to keep its mandate in place following the removal of many federal mandates.

“At this time, the vaccine requirement will remain in effect for VA health care personnel, including VA psychologists, pharmacists, social workers, nursing assistants, physical therapists, respiratory therapists, peer specialists, medical support assistants, engineers, housekeepers, and other clinical, administrative, and infrastructure support employees,” Mr. McDonough wrote to VA employees at the time.

This also includes VA volunteers and contractors. Effectively, this means that any Veterans Health Administration (VHA) employee, volunteer, or contractor who works in VHA facilities, visits VHA facilities, or provides direct care to those we serve will still be subject to the vaccine requirement at this time,” he said. “We continue to monitor and discuss this requirement, and we will provide more information about the vaccination requirements for VA health care employees soon. As always, we will process requests for vaccination exceptions in accordance with applicable laws, regulations, and policies.”

The version of the shots cleared in the fall of 2022, and available through the fall of 2023, did not have any clinical trial data supporting them.

A new version was approved in the fall of 2023 because there were indications that the shots not only offered temporary protection but also that the level of protection was lower than what was observed during earlier stages of the pandemic.

Ms. Manookian, whose group has challenged several of the federal mandates, said that the mandate “illustrates the dangers of the administrative state and how these federal agencies have become a law unto themselves.”

Tyler Durden Sat, 03/09/2024 - 22:10

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Low Iron Levels In Blood Could Trigger Long COVID: Study

Low Iron Levels In Blood Could Trigger Long COVID: Study

Authored by Amie Dahnke via The Epoch Times (emphasis ours),

People with inadequate…

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Low Iron Levels In Blood Could Trigger Long COVID: Study

Authored by Amie Dahnke via The Epoch Times (emphasis ours),

People with inadequate iron levels in their blood due to a COVID-19 infection could be at greater risk of long COVID.

(Shutterstock)

A new study indicates that problems with iron levels in the bloodstream likely trigger chronic inflammation and other conditions associated with the post-COVID phenomenon. The findings, published on March 1 in Nature Immunology, could offer new ways to treat or prevent the condition.

Long COVID Patients Have Low Iron Levels

Researchers at the University of Cambridge pinpointed low iron as a potential link to long-COVID symptoms thanks to a study they initiated shortly after the start of the pandemic. They recruited people who tested positive for the virus to provide blood samples for analysis over a year, which allowed the researchers to look for post-infection changes in the blood. The researchers looked at 214 samples and found that 45 percent of patients reported symptoms of long COVID that lasted between three and 10 months.

In analyzing the blood samples, the research team noticed that people experiencing long COVID had low iron levels, contributing to anemia and low red blood cell production, just two weeks after they were diagnosed with COVID-19. This was true for patients regardless of age, sex, or the initial severity of their infection.

According to one of the study co-authors, the removal of iron from the bloodstream is a natural process and defense mechanism of the body.

But it can jeopardize a person’s recovery.

When the body has an infection, it responds by removing iron from the bloodstream. This protects us from potentially lethal bacteria that capture the iron in the bloodstream and grow rapidly. It’s an evolutionary response that redistributes iron in the body, and the blood plasma becomes an iron desert,” University of Oxford professor Hal Drakesmith said in a press release. “However, if this goes on for a long time, there is less iron for red blood cells, so oxygen is transported less efficiently affecting metabolism and energy production, and for white blood cells, which need iron to work properly. The protective mechanism ends up becoming a problem.”

The research team believes that consistently low iron levels could explain why individuals with long COVID continue to experience fatigue and difficulty exercising. As such, the researchers suggested iron supplementation to help regulate and prevent the often debilitating symptoms associated with long COVID.

It isn’t necessarily the case that individuals don’t have enough iron in their body, it’s just that it’s trapped in the wrong place,” Aimee Hanson, a postdoctoral researcher at the University of Cambridge who worked on the study, said in the press release. “What we need is a way to remobilize the iron and pull it back into the bloodstream, where it becomes more useful to the red blood cells.”

The research team pointed out that iron supplementation isn’t always straightforward. Achieving the right level of iron varies from person to person. Too much iron can cause stomach issues, ranging from constipation, nausea, and abdominal pain to gastritis and gastric lesions.

1 in 5 Still Affected by Long COVID

COVID-19 has affected nearly 40 percent of Americans, with one in five of those still suffering from symptoms of long COVID, according to the U.S. Centers for Disease Control and Prevention (CDC). Long COVID is marked by health issues that continue at least four weeks after an individual was initially diagnosed with COVID-19. Symptoms can last for days, weeks, months, or years and may include fatigue, cough or chest pain, headache, brain fog, depression or anxiety, digestive issues, and joint or muscle pain.

Tyler Durden Sat, 03/09/2024 - 12:50

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