July 19, 2021 -- There are lots of unfounded fears about the COVID-19 vaccines floating around, and one of the most pervasive is the idea that these new shots aren't really vaccines, but that they will somehow change your genes or insert themselves into the DNA of your cells.

You may see people posting on social media about the vaccines being a kind of gene therapy, and they're partly right, but in the end this idea often misses some important details about how the vaccines work. They can't change your genes, and they don't stay in your body for more than a few days.

But plenty of people have distorted the way the vaccines work into something that could sound sinister. For example, in January, the Weston A. Price Foundation, a group that discourages vaccination, hosted a podcast where David Martin, PhD, described by FactCheck.org as a "financial analyst and self-help entrepreneur," called the vaccines gene therapy.

"a vaccine is supposed to trigger immunity. It's not supposed to trigger you to make a toxin," Martin said. "It's not a vaccination."

Except that these shots are vaccines, according to the US Food and Drug Administration (FDA), and they don't cause you to make a toxin.

So where did this idea get started?

"Like many rumors, there's sort of an element of truth," says Beth Thielen, MD, PhD, a pediatric infectious disease specialist at the University of Minnesota Medical School.

But the truth is that the vaccines involve sound science that sounds complicated to most people not educated in the field.

The vaccines made by Pfizer and Moderna use tiny oily envelopes called lipid nanoparticles to slip a single strand of genetic material called messenger RNA (mRNA) into our cells.

The Johnson & Johnson vaccine is slightly different. It uses double-stranded DNA inserted into a common, but inert virus called an adenovirus. This DNA also contains the instructions for building the spike protein. Once inside the cell, these instructions are read and translated into mRNA.

These bits of mRNA go into the jellied liquid called cytoplasm that makes up the body of our cells.

"Where they join about 200,000 other pieces of messenger RNA that are also sitting in every cell's cytoplasm, because our cells make proteins and enzymes all the time," says Paul Offit, MD, director of the vaccine education center at Children's Hospital of Philadelphia.

The mRNA chains are basically work orders that spell out the instructions for making the spike proteins that stud the outside of the coronavirus that cases COVID-19. The virus uses its spikes to dock onto our cells and infect them.

It's one of the viruses' most recognizable features. Our cells read this mRNA and use them to assemble the spikes. The spikes migrate to the outside of our cells where they are recognized and remembered by our immune system.

These spikes, by themselves, are not dangerous. They can't make anyone sick. They are essentially mug shots that help the body recognize and fight off the real perpetrator when it comes along.

The mRNA chains from the vaccines only last for a couple of days before they break down and the pieces are swept away by the body's normal waste disposal system.

Messenger RNA is genetic material, so in that sense, the vaccines are genetically based therapy.

But the FDA classifies them as vaccines, not gene therapy.

"I think people hear that and they think 'Oh my God, You're going to alter my DNA," Offit says. "That's not possible."

For the vaccines to alter a person's genes, Offit explains, the mRNA instructions would have to enter the cell's control center, the nucleus. The nucleus is walled off from the rest of the cell by its own membrane. To get past that membrane, the mRNA would have to have an enzyme called a nuclear access signal, Offit says, "which it doesn't have."

Even if it could get into the nucleus, the single strand of mRNA would have to be translated back into a double stranded DNA.

HIV, the virus that causes AIDS, can do this. It uses an enzyme like reverse transcriptase to insert itself into our chromosomes. The mRNA in the vaccines lacks this enzyme, so it can't turn back into DNA.

The DNA adenovirus used in the Johnson & Johnson vaccine does enter the nucleus of our cells, but it never integrates into our chromosomes.

Even after those two steps, there's a third firewall between the vaccines and our genes: Another enzyme, called an integrase, would be needed to stitch the new DNA into the DNA of our cells. That's also not in the vaccines.

"So the chances are zero that that can happen," Offit says.

One way to think about mRNA is to imagine if a friend wanted to make a delicious salad that you have the recipe for, Thielen says.

"You'd go to your cookbook, you'd copy the recipe on a note card and give it to them," she says. They can make the salad, but they don't have the cookbook, the original cookbook. You didn't change the cookbook, you just gave them a Post-it note or something that's temporary and that's meant to be," she says.

It's true that these are some of the first vaccines to work this way, but the technology was years in the making. The science was given a final push by billions in funding that was made available through Operation Warp Speed.

The vaccines have now been given to millions of people. They are some of the most effective in the world at preventing severe outcomes from COVID infections. So far, they are holding up well against all the viral variants.

While very rare side effects have been linked to the vaccines, so far, the FDA has determined that the benefit from taking one far outweighs these rare risks for most people.

"I've been astonished, actually,at how well it seems to be working. And so, I think it is very exciting from a vaccine development standpoint that we have new tools in our armamentarium to make new vaccines," Thielen says.

But there's still more to learn.

"I think we need to do dedicated studies of this platform to really understand how long the protection lasts and how well does it adapt to other vaccine targets like RSV. I think that remains to be seen," Thielen says.

Medscape Medical News

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Chance That COVID-19 Vaccines Are Gene Therapy? 'Zero' - WebMD

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Friday, July 16, 2021

Results provide hope for children with aromatic L-amino acid decarboxylase deficiency.

A new study published in Nature Communications suggests that gene therapy delivered into the brain may be safe and effective in treating aromatic L-amino acid decarboxylase (AADC) deficiency. AADC deficiency is a rare neurological disorder that develops in infancy and leads to near absent levels of certain brain chemicals, serotonin and dopamine, that are critical for movement, behavior, and sleep. Children with the disorder have severe developmental, mood dysfunction including irritability, and motor disabilities including problems with talking and walking as well as sleep disturbances. Worldwide there have been approximately 135 cases of this disease reported.

In the study, led by Krystof Bankiewicz, M.D., Ph.D., professor of neurological surgery at Ohio State College of Medicine in Columbus, and his colleagues, seven children received infusions of the DDC gene that was packaged in an adenovirus for delivery into brain cells. The DDC gene is incorporated into the cells DNA and provides instructions for the cell to make AADC, the enzyme that is necessary to produce serotonin and dopamine. The research team used magnetic resonance imaging to guide the accurate placement of the gene therapy into two specific areas of the midbrain.

Positron emission tomography (PET) scans performed three and 24 months after the surgery revealed that the gene therapy led to the production of dopamine in the deep brain structures involved in motor control. In addition, levels of a dopamine metabolite significantly increased in the spinal fluid.

The therapy resulted in clinical improvement of symptoms. Oculogyric crises, abnormal upward movements of the eyeballs, often with involuntary movements of the head, neck and body, that can last for hours and are a hallmark of the disease, completely went away in 6 of 7 participants. In some of the children, improvement was seen as early as nine days after treatment. One participant continued to experience oculogyric crises, but they were less frequent and severe.

All of the children exhibited improvements in movement and motor function. Following the surgery, parents of a majority of participants reported their children were sleeping better and mood disturbances, including irritability, had improved. Progress was also observed in feeding behavior, the ability to sit independently, and in speaking. Two of the children were able to walk with support within 18 months after receiving the gene therapy.

The gene therapy was well tolerated by all participants and no adverse side effects were reported. At three to four weeks following surgery, all participants exhibited irritability, sleep problems, and involuntary movements, but those effects were temporary. One of the children died unexpectedly seven months after the surgery. The cause of death was unknown but assessed to be due to the underlying primary disease.

Jill Morris, Ph.D., program director, NIHs National Institute of Neurological Disorders and Stroke (NINDS). To arrange an interview, please contact nindspressteam@ninds.nih.gov

Pearson TS et al., Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons, Nature Communications, July 12, 2021. https://doi.org/10.1038/s41467-021-24524-8

This study was supported by NINDS (R01NS094292, NS073514-01).

The NINDS NINDS is the nations leading funder of research on the brain and nervous system.The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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funded study finds gene therapy may restore missing enzyme in rare disease - National Institutes of Health

ByGina Wadas

Viruses are experts at infiltrating the body, as the SARS-CoV-2 virus (and resulting COVID-19 pandemic) have amply demonstrated. But their efficiency in targeting specific and isolated cells also make them useful drug delivery vehicles, known as viral vectors.

Viral vectors are modified viruses that can act as couriers to transport therapeutic "packages" to specific diseased cells. These packages contain instructions with modified or designed DNA or RNA to correct or supplement a faulty or missing gene. For instance, the Johnson & Johnson COVID-19 vaccine uses viral vectors to transport modified genetic material from the SARS-CoV-2 virus to cells, generating an immune response.

Though viral vector-based gene therapies are among the most advanced treatments for many congenital and acquired diseases, producing them is complex and costly.

"One of the major challenges in viral vector gene therapy is how to improve the quality, purity, and cost of the manufactured viral vectors, so that we can use the smallest possible effective dose, reduce immune side effects, and lower the cost of treatments," said Hai-Quan Mao, associate director and core faculty member of the Institute for NanoBioTechnology. He is also a professor in the departments of Materials Science and Engineering and Biomedical Engineering and a core faculty member at the Translational Tissue Engineering Center.

Hai-Quan Mao

Associate director, Institute for NanoBioTechnology

To address this challenge, Mao and his team are teaming up with Nolan Sutherland, senior scientist at bluebird bio, a Cambridge, Massachusetts-based biotechnology company that develops gene therapies. The partnership started about two years ago when Yizong Hu, a biomedical engineering PhD student under the mentorship of Mao, was at an annual meeting for the American Society for Gene and Cell Therapy presenting his research on a new particle assembly technology. Sutherland heard the presentation and approached Hu to discuss the technology and its application to the production of lentiviral vectors, which are made from a family of viruses that infect people by reverse transcription of their RNA into DNA in their host cells' genome.

Sutherland thought that the Mao team's approach might help streamline transfection, a key step in producing viral vectors. During transfection, a polymer solution is combined with a mixture of DNA plasmids to form transfection particles, a cumbersome procedure involving complicated solution blending and strictly timed dosing.

Mao, Hu, and Yining Zhu, also a biomedical engineering PhD student, developed a more effective and shelf-stable formulation of DNA particles in a ready-to-dose form. They also discovered that size-controlled sub-micron particles are most effective in transfecting cells and producing viral vectors. This production method is based on the team's years of experience in controlling transfection vehicle characteristics to enhance performances and stability.

The team members validated their findings with Sutherland at bluebird bio using that company's bioreactor. They compared the new method with the industry standard, and the results showed improved vector production yield, shelf stability, handling stability, and quality control of the transfection process.

"With the drastic increase in demand for lentiviral vector-based cell therapy products ... this new technology will greatly improve the production quality, consistency, and yield of our therapeutic LVVs," Sutherland said.

The team reported its findings in Nano Letters and is scaling up production with an eye to transferring the technology to the marketplace.

"This work represents a great example how we can partner with corporate collaborators to accelerate the translation of discoveries on the bench to the industry. This type of collaboration with industry provides us opportunities to identify the technical gaps in the engineering solutions that we develop, and fine tune them to better address the real-world problems in a more targeted fashion," Mao said.

According to Sutherland, the partnership with Mao and his team has "allowed bluebird to pursue high risk/reward innovation in a space outside of its core expertise. The team has a keen eye for application to industry which has made the partnership incredibly productive."

Team members say that this new particle engineering technology will find a wide range of applications in the manufacture of a variety of viral vectors for gene and cell therapy applications.

Also contributing to the project are Jordan Green, professor in the Department of Biomedical Engineering and associate member at the INBT, and Sashank Reddy, assistant professor of plastic and reconstructive surgery at Johns Hopkins Medicine, medical director at Johns Hopkins Technology Ventures, and affiliate faculty member at the INBT.

Continued here:
Researchers partner with industry to create better gene therapy tools - The Hub at Johns Hopkins

Scientists from Ohio State University have developed a novel method for delivering gene therapy to specific regions of the brain. Now, they have evidence from a small clinical trial in children that the treatment could address a rare, inherited neurodegenerative disease. And they believe their technique could eventually be used to treat more common brain diseases, like Alzheimers and Parkinsons.

The Ohio State team developed the gene therapy to treat aromatic L-amino acid decarboxylase (AADC) deficiency, which hampers the bodys ability to make dopamine and serotonin and results in developmental delays and a range of motor and behavioral symptoms. The gene therapy uses a viral vector to carry DNA-expressing AADC to the brain.

In seven children with AADC deficiency, the gene therapy boosted the metabolism of dopamine, the researchers reported in Nature Communications. Within three months, six of the children were no longer experiencing oculogyric crises (OGC), which are eye spasms that commonly occur in children with the disorder. After a year, six of the participants had normal head control, the researchers said.

During the trial, the Ohio State team delivered the gene therapy directly to the midbrain, monitoring the spread of the DNA in real time using MRI imaging. They reported dramatic improvements in several symptoms beyond OGC, including sleep disturbances and irritable mood, according to the paper. Improvements in motor function took longer to emerge, they wrote, but were markedly better than what would normally be expected to occur in the natural course of AADC deficiency for patients in this age range (49 years) who have severe motor impairment.

RELATED: Taking gene therapy to the masses with innovations in diabetes, Alzheimer's and more

The ability to deliver gene therapy directly to the brainand monitor its effects with advanced imagingcould enhance efforts to treat a range of neurodegenerative disorders, said Krystof Bankiewicz, M.D., Ph.D., neurological surgery professor at the Ohio State College of Medicine, in a statement.

In fact, a handful of companies are working toward that goal. They include Lexeo Therapeutics, which is developing a gene therapy to deliver the APOE2 gene into the central nervous system in the hopes that it will slow the development of Alzheimers in people with two copies of the the high-risk APOE4 variant.

Another company examining brain-delivered gene therapy is VectorY, which recently raised $38 million to advance its work. VectorY is using viruses to carry genes into the brain that can encode therapeutic antibodies. It is using the newly raised funding to complete preclinical work on therapies for amyotrophic lateral sclerosis and Alzheimers.

Based on the success of their early-stage trial in AADC deficiency, the Ohio State researchers are planning clinical trials of their brain-delivered gene therapy in other incurable, debilitating diseases, they said.

The gene therapy approach described here represents many years of careful work to develop and to understand effective ways to deliver gene therapy to the brain, they wrote in the study. This work provides a framework for the treatment of other human CNS genetic diseases, and iterative refinement of the individual components of this approach will facilitate broader application.

More here:
Gene therapy delivered to the brain shows promise in children with rare neurodegenerative disease - FierceBiotech