Potential 'fountain of youth' gene found

Gene helps prevent heart attack, stroke; may offer way to block effects of aging

Date:

May 17, 2016

Source:

University of Virginia Health System

Summary:

A gene that scientific dogma insists is inactive in adults actually plays a vital role in preventing the underlying cause of most heart attacks and strokes, researchers have determined. The discovery opens a new avenue for battling those deadly conditions, and it raises the tantalizing prospect that doctors could use the gene to prevent or delay at least some of the effects of aging.

FULL STORY

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This is an atherosclerotic lesion. Such lesions can rupture and cause heart attacks and strokes.

Credit: UVA School of Medicine

A gene that scientific dogma insists is inactive in adults actually plays a vital role in preventing the underlying cause of most heart attacks and strokes, researchers at the University of Virginia School of Medicine have determined. The discovery opens a new avenue for battling those deadly conditions, and it raises the tantalizing prospect that doctors could use the gene to prevent or delay at least some of the effects of aging.

"Finding a way to augment the expression of this gene in adult cells may have profound implications for promoting health and possibly reversing some of the detrimental effects with aging," said researcher Gary K. Owens, PhD, director of UVA's Robert M. Berne Cardiovascular Research Center.

Unexpected Protective Effect

The gene, Oct4, plays a key role in the development of all living organisms, but scientists have, until now, thought it was permanently inactivated after embryonic development. Some controversial studies have suggested it might have another function later in life, but the UVA researchers are the first to provide conclusive evidence of that: Owens and his colleagues have determined the gene plays a critical protective role during the formation of atherosclerotic plaques inside blood vessels. The rupturing of these plaques is the underlying cause of many heart attacks and strokes.

The researchers found that Oct4 controls the movement of smooth muscle cells into protective fibrous "caps" inside the plaques -- caps that make the plaques less likely to rupture. The researchers also have provided evidence that the gene promotes many changes in gene expression that are beneficial in stabilizing the plaques. This is exciting, because studies suggest that it may be possible to develop drugs or other therapeutic agents that target the Oct4 pathway as a means to reduce the incidence of heart attacks or stroke. "Our findings have major implications regarding possible novel therapeutic approaches for promoting stabilization of atherosclerotic plaques," said Olga A. Cherepanova, PhD, a senior research scientist in Owens' lab.

One surprising finding from UVA's research: When the researchers blocked the effect of Oct4 in mice, they thought the atherosclerotic plaques might become smaller, because of the reduced number of smooth muscle cells inside. Instead, the plaques grew larger, less stable and more dangerous, stuffed with lipids, dead cells and other damaging components.

Advancing Regenerative Medicine

While UVA's research has focused on how Oct4 offers cardiovascular protection, Owens and his colleagues believe the gene could also prove critical to the field of regenerative medicine, which investigates the growth and replacement of tissues and organs. The researchers believe that Oct4 and its family of target genes are activated in other somatic cells -- the non-reproductive cells in the body -- and play a key role in the cells' ability to repair damage and heal wounds. Studies to test this are under way in Owens' lab.

Oct4 is one of the "stem cell pluripotency factors" described by Shinya Yamanaka, MD, PhD, for which he received the 2012 Nobel Prize. His lab and many others have shown that artificial over-expression of Oct4 within somatic cells grown in a lab dish is essential for reprogramming these cells into induced pluripotential stem cells, which can then develop into any cell type in the body or even an entire organism.

The UVA researchers suspect that at least some of the detrimental effects of aging, including the increased possibility of a plaque rupture, stem from a decrease in the body's ability to reactivate Oct4. "Finding a way to reactivate this pathway may have profound implications for health and aging," Owens said. "We think this is just the tip of the iceberg for controlling plasticity of somatic cells, and this could impact many human diseases and the field of regenerative medicine. Who knows, this may end up being the 'fountain-of-youth gene,' a way to revitalize old and worn-out cells. Only time will tell."

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Story Source:

The above post is reprinted from materials provided by University of Virginia Health System. Note: Materials may be edited for content and length.

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Journal Reference:

1. Olga A Cherepanova, Delphine Gomez, Laura S Shankman, Pamela Swiatlowska, Jason Williams, Olga F Sarmento, Gabriel F Alencar, Daniel L Hess, Melissa H Bevard, Elizabeth S Greene, Meera Murgai, Stephen D Turner, Yong-Jian Geng, Stefan Bekiranov, Jessica J Connelly, Alexey Tomilin, Gary K Owens. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nature Medicine, 2016; DOI:10.1038/nm.4109

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Antibody therapy opens door to potential new treatment for HIV

The development of antiretroviral therapy, a combination of drugs that slows the replication of HIV in the body, has transformed the treatment of this infection. What was once a certain death sentence is now a chronic condition that people can live with for decades.

But this therapy has drawbacks. There are side effects, including kidney problems, decreased bone density, and gastrointestinal problems. And if a person discontinues his or her treatment, even missing a few doses, the level of the virus in the body is able to rebound quickly.

Researchers from The Rockefeller University, along with collaborators from the University of Cologne, are developing a new kind of treatment, an antibody-based drug that may provide a better strategy for long-term control of HIV. Recent findings from a Phase 1 clinical trial, published on May 5 inScience, offer new insights about how the antibody functions.

"This study provides evidence that a single dose of an antibody stimulates patients' immune response, enabling them to make new or better antibodies against the virus," explains Till Schoofs, a postdoctoral fellow and one of the study's first authors. Schoofs is a member of the Laboratory of Molecular Immunology, led by Michel Nussenzweig, Zanvil A. Cohn and Ralph M. Steinman Professor, who is the study's senior author.

"We reported last year that this treatment can greatly reduce the amount of virus that's present in someone's blood," Dr. Schoofs adds, "but we wanted to follow the patients for a longer period of time to study how their immune systems were adapting to the new therapy."

Neutralizing a deadly virus

The molecule used in the research, 3BNC117, is called a broadly neutralizing antibody because it has the ability to fight a wide range of HIV strains. Johannes Scheid, a student in Nussenzweig's lab, isolated it several years ago from an HIV-infected patient whose immune system had an exceptional ability to neutralize HIV in the blood by preventing the virus from infecting and destroying a specific type of immune cells, called CD4 cells, in patients. The destruction of CD4 cells is a hallmark of AIDS.

Early studies showed that 3BNC117 can neutralize more than 80 percent of HIV strains that are found around the world. The investigators therefore theorized that giving the antibody to patients would help them to fight the virus as well.

The clinical trial included 15 patients who had high levels of the virus in their blood, and 12 other patients whose virus levels were being controlled with antiretroviral therapy (ART). The majority of trial participants were treated at The Rockefeller University Hospital. The patients were infused with a single dose of 3BNC117 and were monitored over a six-month period.

The investigators found that 14 out of 15 patients who had high levels of the virus at the time they were given the antibody were making new antibodies that were able to neutralize a number of different strains of HIV.

"It usually takes several years for the body to begin to make good antibodies against HIV," Schoofs says. "So there might be an even better effect later on, especially if patients are given more than one dose of 3BNC117."

The next steps in this research are to test 3BNC117 in combination with other antibodies that target HIV, to determine whether an even stronger antiviral effect can be found. The researchers are also conducting a Phase 2 trial in which patients receiving ART are switched to antibody treatment.

Exploring an antibody's function

In a companion study published in the same issue of Science, the investigators wanted to determine what further benefits treatment with 3BNC117 may have over ART.

They looked at the results of the clinical trial, and used a mathematical model of HIV dynamics to predict how the patients' levels of HIV would have fared if 3BNC117 did nothing else than to neutralize HIV in the blood and block new infection. Their analysis showed that neutralization of the virus alone doesn't explain the steep drop in the virus levels observed in patients--leading the scientists to suspect that there must be another component to the antibody's efficacy.

Working in a mouse model, the researchers saw evidence that 3BNC117 was able to engage the animals' immune cells and accelerate their clearance of HIV-infected cells. "This shows that the antibody not only can exert pressure on the virus, but also can shorten the survival of infected cells," says first author Ching-Lan Lu, a visiting student in Dr. Nussenzweig's lab. "Our results explain why post-exposure prophylaxis"--short-term treatment after exposure to HIV to reduce infection--"with antibodies is more effective than ART in our mouse models."

In addition, they could potentially make it possible to address a major obstacle to curing HIV: the virus's ability to establish a latent reservoir soon after infection, and so hide out in the body and evade treatment. A follow-up clinical study is currently underway at Rockefeller to assess whether offering antibody drugs to patients receiving ART can help reduce or alter their HIV reservoirs.

Story Source:

The above story is based on materials provided by Rockefeller University. Note: Materials may be edited for content and length.

Journal References:

T. Schoofs, F. Klein, M. Braunschweig, E. F. Kreider, A. Feldmann, L. Nogueira, T. Oliveira, J. C. C. Lorenzi, E. H. Parrish, G. H. Learn, A. P. West, P. J. Bjorkman, S. J. Schlesinger, M. S. Seaman, J. Czartoski, M. J. McElrath, N. Pfeifer, B. H. Hahn, M. Caskey, M. C. Nussenzweig.HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science, 2016; DOI: 10.1126/science.aaf0972

C.-L. Lu, D. K. Murakowski, S. Bournazos, T. Schoofs, D. Sarkar, A. Halper-Stromberg, J. A. Horwitz, L. Nogueira, J. Golijanin, A. Gazumyan, J. V. Ravetch, M. Caskey, A. K. Chakraborty, M. C. Nussenzweig.Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science, 2016; DOI: 10.1126/science.aaf1279

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Chemists develop an ultra-sensitive test for cancers, HIV

A common theme in medicine is that detecting a disease early on can lead to more effective treatments. This relies partly on luck that the patient gets screened at the right time, but more important is that the testing techniques are sensitive enough to register the minuscule hints that diseases leave in the blood stream.

A new technique developed by a team of chemists at Stanford has shown promise to be thousands of times more sensitive than current techniques in lab experiments, and it is now being put to test in real-world clinical trials.

When a disease -- whether it's a cancer or a virus like HIV -- begins growing in the body, the immune system responds by producing antibodies. Fishing these antibodies or related biomarkers out of the blood is one way that scientists infer the presence of a disease. This involves designing a molecule that the biomarker will bind to, and which is adorned with an identifying "flag." Through a series of specialized chemical reactions, known as an immunoassay, researchers can isolate that flag, and the biomarker bound to it, to provide a proxy measurement of the disease.

The new technique, developed in the lab of Carolyn Bertozzi, a professor of chemistry at Stanford, augments this standard procedure with powerful DNA screening technology. In this case, the chemists have replaced the standard flag with a short strand of DNA, which can then be teased out of the sample using DNA isolation technologies that are far more sensitive than those possible for traditional antibody detections.

"This is spiritually related to a basic science tool we were developing to detect protein modifications, but we realized that the core principles were pretty straightforward and that the approach might be better served as a diagnostic tool," said Peter Robinson, a co-author on the study and graduate student in Bertozzi's group.

The researchers tested their technique, with its signature DNA flag, against four commercially available, FDA-approved tests for a biomarker for thyroid cancer. It outperformed the sensitivity of all of them, by at least 800 times, and as much as 10,000 times. By detecting the biomarkers of disease at lower concentrations, physicians could theoretically catch diseases far earlier in their progression.

"The thyroid cancer test has historically been a fairly challenging immunoassay, because it produces a lot of false positives and false negatives, so it wasn't clear if our test would have an advantage," Robinson said. "We suspected ours would be more sensitive, but we were pleasantly surprised by the magnitude."

Putting basic research to use in a clinical setting has been a focus of Bertozzi's since she arrived at Stanford.

"I moved to Stanford with the anticipation that translation of my students' innovations to clinically impactful products and technologies would be enabled," said Bertozzi, who is a faculty fellow of Stanford ChEM-H, as well as a professor, by courtesy, of radiology and of chemical and systems biology. "That goal is being delightfully fulfilled."

Based on the success of the thyroid screening, the group has won a few grants to advance the technique into clinical trials. One trial underway in collaboration with the nearby Alameda County Public Health Laboratory will help evaluate the technique as a screening tool for HIV. Early detection and treatment of the virus can help ensure that its effects on the patient are minimized and reduce the chance that it is transmitted to others. This effort is supported by a pilot grant from Stanford-Spectrum, funded by the National Center for Advancing Translational Sciences at the National Institutes of Health.

"Many of our collaborators are excited that the test can be readily deployed in their lab," said co-author Cheng-ting "Jason" Tsai, a graduate student in Bertozzi's group. "In contrast to many new diagnostic techniques, this test is performed on pre-existing machines that most clinical labs are already familiar with."

The researchers are also pursuing tests for Type 1 diabetes, for which early detection could help patients manage the disease with fewer side effects.

The research is published in the journalACS Central Science. The study was co-authored by Carole Spencer of the University of Southern California. This work was supported in part by a grant from the National Institutes of Health.

Story Source:

The above story is based on materials provided by Stanford University. Note: Materials may be edited for content and length.

Journal Reference:

Cheng-ting Tsai, Peter V. Robinson, Carole A. Spencer, Carolyn R. Bertozzi.Ultrasensitive Antibody Detection by Agglutination-PCR (ADAP). ACS Central Science, 2016; DOI: 10.1021/acscentsci.5b00340

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