Tag Archives: Viral Vector

Experimental decoy provides long-term protection from SARS-Cov-2 infection

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An experimental “decoy” provided long-term protection from infection by the pandemic virus in mice, a new study finds.

Led by researchers at NYU Grossman School of Medicine, the work is based on how the virus that causes COVID-19, SARS-CoV-2, uses its spike protein to attach to a protein on the surface of the cells that line human lungs. Once attached to this cell surface protein, called angiotensin converting enzyme 2 (ACE2), the virus spike pulls the cell close, enabling the virus to enter the cell and hijack its machinery to make viral copies.

Earlier in the pandemic, pharmaceutical companies designed monoclonal antibodies to glom onto the spike and neutralize the virus. Treatment of patients soon after infection was successful in preventing hospitalization and death. However the virus rapidly evolved through random genetic changes (mutations) that altered the spike’s shape enough to evade even combinations of therapeutic monoclonal antibodies. Thus, such antibodies, which neutralized early variants, became about 300 times less effective against more recent delta and omicron variants.

Published online this week in the Proceedings of the National Academy of Sciences, the study describes an alternative approach from which the virus cannot escape. It employs a version of ACE2, the surface protein to which the virus attaches, which, unlike the natural, cell-bound version, is untethered from the cell surface. The free-floating “decoy” binds to the virus by its spikes so that it can no longer attach to ACE2 on cells in airways. Unlike the monoclonal antibodies, which are shaped to interfere with a certain spike shape, the decoy mimics the spike’s main target, and the virus cannot easily evolve away from binding to ACE2 and still invade cells.

Treatment with the decoy, either by injection or droplets in the nose, protected 100 percent of the study mice when they were infected in the lab with an otherwise lethal dose of SARS-CoV-2. The decoy lowered the virus load in the mice by 100,000-fold, while mice exposed to a non-active control treatment died. Decoy treatment of mice that were already infected with SARS-CoV-2 caused a rapid drop in viral levels and return to health. This suggests that the decoy could be effective as a therapy post-infection, similar to monoclonal antibodies, the researchers say.

What is remarkable about our study is that we delivered the decoy using a harmless, adeno-associated virus or AAV vector, a type of gene therapy that has been found in previous studies to be safe for use in humans. The viral vector instructs cells in the body to produce the decoy so that the mouse or person is protected long-term, without the need for continual treatment.”

Nathanial Landau, PhD, senior study author, professor, Department of Microbiology at NYU Langone Health

Administered with the vector, says Landau, the treatment caused cells, not only to make the decoy, but to continue making it for several months, and potentially for years.

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Importantly, vaccines traditionally include harmless parts of a virus they are meant to protect against, which trigger a protective immune response should a person later be exposed. Vaccines are less effective, however, if a person’s immune system has been compromised, by diseases like cancer or in transplant patients treated with drugs that suppress the immune response to vaccination. Decoy approaches could be very valuable for immunocompromised patients globally, adds Landau.

Future pandemics

For the new study, the research team made key changes to a free ACE2 receptor molecule, and then fused the spike-binding part of it to the tail end of an antibody with the goal of strengthening its antiviral effect. Attaching ACE2 to the antibody fragment to form what the team calls an “ACE2 microbody” increases the time that the molecule persists in tissues (its half-life). The combination also causes the molecules to form dimers, mirror-image molecular pairs that increase the strength with which the decoy attaches to the viral spike.

Whether administered via injection into muscle, or through droplets in the nasal cavity, the study’s AAV vectors provided mice with long-lasting protection COVID infection, including the current Omicron variants.

The approach promises to be effective even if another coronavirus, a type of virus common in birds and bats or apes, were to be transferred to humans in the future, an event termed “zoonosis.” As long as the future virus also uses ACE2 to target cells, the decoy would be ready for “off-the-shelf” soon after an outbreak. If the virus were to somehow switch its receptor a different protein on the surface of lung cells, the decoy could be modified to target the new virus, says Landau.

Along with Landau, the study authors were Takuya Tada and Julia Minnee in the Department of Microbiology at NYU Grossman School of Medicine. The study was supported by a grant from the National Institutes of Health.

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Journal reference:

Tada, T., et al. (2023) Vectored immunoprophylaxis and treatment of SARS-CoV-2 infection in a preclinical model. PNAS. doi.org/10.1073/pnas.2303509120.

Simple blood tests for telomeric protein could provide a valuable screen for certain cancers

Once thought incapable of encoding proteins due to their simple monotonous repetitions of DNA, tiny telomeres at the tips of our chromosomes seem to hold a potent biological function that’s potentially relevant to our understanding of cancer and aging.

Reporting in the Proceedings of the National Academy of Science, UNC School of Medicine researchers Taghreed Al-Turki, PhD, and Jack Griffith, PhD, made the stunning discovery that telomeres contain genetic information to produce two small proteins, one of which they found is elevated in some human cancer cells, as well as cells from patients suffering from telomere-related defects.

Based on our research, we think simple blood tests for these proteins could provide a valuable screen for certain cancers and other human diseases. These tests also could provide a measure of ‘telomere health,’ because we know telomeres shorten with age.”

Jack Griffith, PhD, the Kenan Distinguished Professor of Microbiology and Immunology and Member of the UNC Lineberger Comprehensive Cancer Center

Telomeres contain a unique DNA sequence consisting of endless repeats of TTAGGG bases that somehow inhibit chromosomes from sticking to each other. Two decades ago, the Griffith laboratory showed that the end of a telomere’s DNA loops back on itself to form a tiny circle, thus hiding the end and blocking chromosome-to-chromosome fusions. When cells divide, telomeres shorten, eventually becoming so short that the cell can no longer divide properly, leading to cell death.

Scientist first identified telomeres about 80 years ago, and because of their monotonous sequence, the established dogma in the field held that telomeres could not encode for any proteins, let alone ones with potent biological function.

In 2011 a group in Florida working on an inherited form of ALS reported that the culprit was an RNA molecule containing a six-base repeat which by a novel mechanism could generate a series of toxic proteins consisting of two amino acids repeating one after the other. Al-Turki and Griffith note in their paper a striking similarity of this RNA to the RNA generated from human telomeres, and they hypothesized that the same novel mechanism might be in play.

They conducted experiments – as described in the PNAS paper – to show how telomeric DNA can instruct the cell to produce signaling proteins they termed VR (valine-arginine) and GL (glycine-leucine). Signaling proteins are essentially chemicals that trigger a chain reaction of other proteins inside cells that then lead to a biological function important for health or disease.

Al-Turki and Griffith then chemically synthesized VR and GL to examine their properties using powerful electron and confocal microscopes along with state-of-the-art biological methods, revealing that the VR protein is present in elevated amounts in some human cancer cells, as well as cells from patients suffering from diseases resulting from defective telomeres.

“We think it’s possible that as we age, the amount of VR and GL in our blood will steadily rise, potentially providing a new biomarker for biological age as contrasted to chronological age,” said Al-Turki, a postdoctoral researcher in the Griffith lab. “We think inflammation may also trigger the production of these proteins.”

Griffith noted, “When you go against current thinking, you are usually wrong because you are bucking many people who’ve worked so diligently in their fields. But occasionally scientists have failed to put observations from two very distant fields together and that’s what we did. Discovering that telomeres encode two novel signaling proteins will change our understanding of cancer, aging, and how cells communicate with other cells.

“Many questions remain to be answered, but our biggest priority now is developing a simple blood test for these proteins. This could inform us of our biological age and also provide warnings of issues, such as cancer or inflammation.”

Journal reference:

Al-Turki, T., et al. (2023) Mammalian Telomeric RNA (TERRA) can be translated to produce valine-arginine and glycine-leucine dipeptide repeat proteins. PNAS. doi.org/10.1073/pnas.2221529120.