For years, doctors have associated the BRCA1 and BRCA2 gene mutations with an increased risk of breast cancer.

But researchers at Texas A&M University have now identified another gene that may have an impact on breast cancer—associated with the body’s circadian rhythm.

Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM) professor Weston Porter and his team have found that Period 2 (Per2), a regulatory mechanism within each cell’s peripheral clock, plays a crucial function in mammalian mammary gland development and that when suppressed, Per2 leads to severely disrupted gland development in mice.

The findings, published in the scientific journal Development, add to a growing list that ties disruptions to our circadian rhythm—that is, the “central clock” mechanism in our brains—to a higher risk of cancer progression, obesity, some neuromuscular diseases, and other impairments, including jetlag.

Circadian rhythm is controlled by the suprachiasmatic nucleus (SCN) in the brain’s anterior hypothalamus. In addition to coordinating our sleep patterns, the SCN coordinates the other peripheral clocks in our body, which run on a 24-hour cycle that corresponds with each day.

“Not only do we have a central clock, but every one of our cells has one of these peripheral clocks and they’re in coordination with the central clock,” Porter said. “When you wake up in the morning and see light, the light goes right into the brain and it triggers this molecular mechanism that regulates the (circadian rhythm) process.”

In their study, Porter’s team evaluated Per2, which provides the “negative feedback,” or counterbalance, to the circadian rhythm process.

“The negative and positive feedback mechanisms are constantly in balance, going up and down. One’s up during the day, the other one’s up at night—they oscillate right at 24 hours—but when you see light, that resets it in the morning,” Porter said. “WhenPer2 comes back, it suppresses another gene called BMAL or CLOCK.”

Their finding—that Per2 has a crucial function outside of timekeeping in mammalian mammary gland development where Per2plays a role in cell differentiation and identity—describes a potentially important role for Per2 in breast cancer. Per2 expression is lost in a large percentage of mammary tumors, which suggests it may have protective effects.

“We discovered that these glands have what we call a kind of a bipotent phenotype; they’re actually halfway to cancer,” Porter said. “They’ve already have many of the characteristics you would see in a premalignant cell.

“We started to look at the mechanism associated with that and found that the stem cell markers associated with a loss of Per2are more basal, which is characteristic of more invasive cancer,” he said. “This reinforces the idea that Per2 is functioning as a tumor suppressor gene associated with cell identity.”

In addition to disruption of the developing mammary gland, Porter also saw the same defect in transplant studies, showing that it is Per2, and not just the central clock itself, that is responsible for the lack of mammary ductal growth in the developing gland.

Their next step is to revisit studies that correlate working a night shift with an increased risk of breast cancer.

“Right now, we are investigating how our findings relate to humans,” Porter said. “There are studies out there showing a relationship between decreased levels of Per2 and certain types of breast cancer, which are more invasive. So, we believe that there is a direct relationship.”

Understanding circadian rhythm and its effects on the body have become increasingly important to the science community. The 2017 Nobel Prize for Physiology or Medicine was awarded to researchers for discoveries of the molecular mechanisms controlling the circadian rhythm, and the National Cancer Institute recently named the role of circadian rhythms in cancer as one of their 12 provocative questions for the year.

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For more information about the Texas A&M College of Veterinary Medicine & Biomedical Sciences, please visit our website at vetmed.tamu.edu or join us on Facebook, Instagram, and Twitter.

Contact Information: Megan Palsa, Executive Director of Communications, Media & Public Relations, Texas A&M College of Veterinary Medicine & Biomedical Science; mpalsa@cvm.tamu.edu; 979-862-4216; 979-421-3121 (cell)

Viruses have a very limited set of genes and, therefore, must use the cellular machineries of their hosts for most parts of their growth.

In a new study, scientists at Texas A&M and Uppsala universities have discovered a specific host protein that many viruses use for their transport within the cell.

The human gene, ZC3H11A, is found in all vertebrates and is expressed essentially in all human cells; the gene has been known for about 20 years, but its functional importance has been unknown.

The team, led by Texas A&M professor Leif Andersson, however, has discovered that ZC3H11A is critical for the replication of multiple medically important viruses—including adenovirus, influenza virus, HIV, and herpes simplex virus—which opens up new possibilities for the development of new broad-spectrum antiviral therapies.

The discovery was published April 2 in the Proceedings of the National Academy of Sciences (USA).

With modern DNA sequencing technologies, it is relatively easy to identify all genes coding for proteins in an organism, but it is often much more challenging to really understand the cellular function of proteins, according Andersson, professor of animal genomics in the Texas A&M College of Veterinary Medicine & Biomedical Sciences’ (CVM) Department of Veterinary Integrative Biosciences (VIBS) and professor of functional genomics at Sweden’s Uppsala University.

The discovery is the result of a project by Uppsala doctoral student Shady Younis, who used the gene-editing tool CRISPR-Cas9 to inactivate the ZC3H11A gene in a human cell line; initially, he found that the inactivation of ZC3H11A had little effect, showing that it is not essential for the growth of these human cells.

But while discussing his finding with fellow doctoral student Wael Kamel, Younis decided to challenge the cells lacking ZC3H11A with a virus infection.

To their surprise, there was a drastic reduction of the growth of adenovirus (a group of viruses that can infect the tissue linings of the respiratory tract, eyes, intestines, urinary tract, and nervous system) in the cells lacking ZC3H11A, compared with cells expressing the protein.

The team has now demonstrated that at least four different viruses that replicate in the host cell nucleus are dependent on the ZC3H11A protein for their efficient growth; these viruses need ZC3H11A for the transport of virus RNA from the nucleus to the cytoplasm, where the virus proteins will be produced before the viruses can exit the cell and infect other cells, Kamel said.

“This serendipitous discovery is an excellent example of how a good scientific environment can inspire scientists to collaborative efforts that may lead to important scientific discoveries,” Andersson said.

The group also has demonstrated that ZC3H11A is a stress-induced RNA binding protein and appears to be part of a previously unknown mechanism for how cells handle stress.

The observation that the amount of ZC3H11A protein increases during a virus infection was a very surprising finding since viruses typically shut down host-cell protein expression to favor virus production, Andersson said.

“Our data suggest that nuclear-replicating viruses have hijacked a cellular mechanism for RNA transport activated during stress for their own advantage,” he said.

The spread of the influenza virus that has severely impacted people around the world proves there is a strong need to develop new antiviral drugs; a major goal for the team is now to test if they can block how viruses take advantage of the function of the ZC3H11A protein and if this will impair virus growth in living animals, not only in cells as they have proven in the current study, Andersson said.

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For more information about the Texas A&M College of Veterinary Medicine & Biomedical Sciences, please visit our website at vetmed.tamu.edu or join us on Facebook, Instagram, and Twitter.

Contact Information: Megan Palsa, Executive Director of Communications, Media & Public Relations, Texas A&M College of Veterinary Medicine & Biomedical Science; mpalsa@cvm.tamu.edu; 979-862-4216; 979-421-3121 (cell)

College Station, Texas — The U.S. Food and Drug Administration has granted orphan-drug designation to GTX-101 for the treatment of Angelman syndrome, a rare

neurogenetic disorder that affects approximately 1 in 15,000 people. GTX-101 is the first drug candidate for startup GeneTx Biotherapeutics, LLC (GeneTx).

“No approved treatments for Angelman syndrome exist today,” said Allyson Berent, GeneTx chief science officer. “The FDA’s orphan-drug designation for GTX-101 highlights the significant need for treatments for individuals with Angelman syndrome, and we believe that targeted delivery of GTX-101 represents a promising, novel approach to treat this devastating disorder.”

Angelman syndrome (AS) is caused by a loss of function of the maternally inherited UBE3A gene. Symptoms of AS include developmental delay, impaired motor function, loss of speech and epilepsy.

GTX-101 is an investigational antisense oligonucleotide designed to inhibit transcription of the UBE3A-AS across the paternal allele of UBE3A. In vitro studies show that as a result of this inhibition, transcription of the paternal UBE3A gene is restored in neurons of the central nervous system.

An antisense oligonucleotide is a synthetic string of nucleic acids that interferes with the normal processing of a target gene to, for example, turn on or turn off expression of a target gene or to alter the splicing pattern of the gene. Clinical trials have shown promising results using antisense oligonucleotides to treat neurogenetic disorders for spinal muscular atrophy and amyotrophic lateral sclerosis.

“This is a new area of medicine, known as a targeted therapy,” said Scott Dindot, Ph.D., associate professor in the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM). “Historically, clinicians have treated symptoms of a disease or disorder with medication but not the cause of the condition. A targeted therapy goes after the cause of the condition and attempts to fix it.”

GeneTx entered into a worldwide license agreement with The Texas A&M University System and a research collaboration agreement with Texas A&M AgriLife Research, under which GeneTx hopes to further develop and commercialize this novel antisense oligonucleotide as a targeted therapy for patients with the disorder.

“The FDA’s orphan drug designation for GTX-101 is an important next step in bringing effective treatments to individuals with Angelman syndrome,” said Paula Evans, GeneTx chief executive officer. “Activation of the normally silent paternal UBE3A gene has the potential to mitigate many of the disorder’s debilitating symptoms.”

The Orphan Drug Act became law in 1983. Fewer than 5,000 applicants have received this special designation, according to the FDA website. Rare conditions are often described as orphan diseases or disorders when there are few or no treatment options. There are about 7,000 known orphan diseases in the United States.

The FDA’s Orphan Drug Designation program provides orphan status to drugs and biologics that are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases, or disorders that affect fewer than 200,000 people in the United States.

The designation allows the sponsor of the drug to be eligible for various incentives, including a seven-year period of U.S. marketing exclusivity upon regulatory approval of the drug, as well as tax credits for clinical research costs, annual grant funding, clinical trial design assistance, and the waiver of Prescription Drug User Fee Act (PDUFA) filing fees.

About GeneTx Biotherapeutics

GeneTx Biotherapeutics, LLC, is a start-up company dedicated to developing and commercializing safe and effective therapeutics for the treatment of Angelman syndrome.

About Angelman Syndrome

Angelman syndrome (AS) is a rare, neurogenetic disorder caused by a loss of function of the maternally inherited UBE3A gene on the 15th chromosome. UBE3A is an imprinted gene where only the maternal copy is expressed in neurons of the central nervous system. Imprinting of UBE3A is regulated by expression of the paternally expressed UBE3A antisense transcript (UBE3A-AS). Individuals with Angelman syndrome generally have developmental delay, balance issues, motor impairment and debilitating seizures. Some people with AS never walk. Most do not speak. Anxiety and disturbed sleep can be serious challenges among those with AS. While individuals with AS have a normal lifespan, they require continuous care and are unable to live independently. Typical characteristics of AS are not usually evident at birth. Individuals with AS have feeding difficulties as infants and noticeable delayed development around 6-12 months of age. They need intensive therapies to help develop functional skills. In most cases, AS isn’t genetically inherited. Angelman syndrome affects all races and genders. It is often misdiagnosed as autism or cerebral palsy. There is an unmet clinical need for individuals with AS in the areas of motor functioning, communication, behavior and sleep. For more information about Angelman syndrome, please visit CureAngelman.org.

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For more information about the Texas A&M College of Veterinary Medicine & Biomedical Sciences, please visit our website at vetmed.tamu.edu or join us on Facebook, Instagram, and Twitter.

Contact Information: Megan Palsa, Executive Director of Communications, Media & Public Relations, Texas A&M College of Veterinary Medicine & Biomedical Science; mpalsa@cvm.tamu.edu; 979-862-4216; 979-421-3121 (cell)

Weihsueh Chiu, a professor in the Texas A&M College of Veterinary Medicine and Biomedical Sciences’ (CVM) Department of Veterinary Integrative Biosciences (VIBS), has received a $700,000 grant from the National Academies of Sciences, Engineering, and Medicine’s Gulf Research Program (GRP).

Chiu’s project on “Prioritizing Risks from Oil Spills: Supporting Decisions with Read-Across Using 21st Century Exposure and Toxicological Sciences” was one of seven projects from researchers across the country funded through the GRP, the National Academies announced on Jan. 24.

“This project further expands Texas A&M’s commitment to using cutting-edge research and technologies to address the impacts of disasters–in this case, oil spills,” Chiu said. “We are bringing together a world-class, interdisciplinary team that reaches well beyond CVM, including researchers at the Texas A&M School of Public Health and Geochemical & Environmental Research Group, as well as Pacific Northwest National Labs, and the consulting firm Center for Toxicology and Environmental Health.”

For the project, Chiu and his collaborators will use new approaches and technologies in exposure science and toxicology to try to predict the toxicity of substances to which people can be exposed during and after an oil spill.

Because an oil spill can involve a complex mix of interacting substances and environmental factors, which then produces many unknowns that are either difficult or not currently possible to account for, the team will work to address existing limitations and improve assessment and decision-making processes relating to public health risks resulting from oil spills.

“The project will build on and leverage several other recently-initiated projects, including the Texas A&M Superfund Research program and the Institute for Sustainable Communities,” Chiu said. “A key feature of all of these projects is their engagement with local communities and decision-makers involved in disaster response and recovery throughout the research process, so as to accelerate the translation of research into actual practice.”

“This project also will demonstrate the importance of engaging partners like local public health departments in Harris and Galveston Counties to ensure that research is effectively translated into policy and practice to reduce the health impacts of oil spills,” said project collaborator Jennifer Horney, department head and associate professor in the Texas A&M School of Public Health’s Department of Epidemiology & Biostatistics.

The project is one of two funded under the “Improving Risk-Based Evaluations to Support a Public Health Response to the Next Oil Spill” category, for projects focused on improving the information available to decision-makers for evaluating public health risks resulting from oil spills.

“Many decisions relating to public health risks are made following a disaster such as an oil spill,” said Chris Rea, associate program officer for the GRP’s Thriving Communities Initiative. “Risk assessment science inherently involves numerous uncertainties, though, and decisions are limited by what we actually know about potential hazards. The Academies’ report highlighted recent advances that could be used to improve the science behind hazard identification, exposure assessment, and risk characterization, and these two projects are working to apply some of those advances for use in assessing oil spill public health risks.”

The GRP funding competition was specifically geared toward projects that would bring researchers and practitioners together to transfer knowledge and work jointly on efforts that advance both science and its application. All awarded projects were selected after an external peer-review process.

“This funding opportunity is an example of how the Gulf Research Program takes advantage of a core strength of the National Academies – to supply expert consensus on using science to address real-world problems,” said Evonne Tang, the GRP’s director of external funding opportunities. “Two recent reports on topics central to the GRP’s mission were the basis of this grant competition, and the awards direct funding toward efforts that will quickly begin to address the recommendations in those reports.”

The GRP is an independent, science-based program founded in 2013 as part of legal settlements with the companies involved in the 2010 Deepwater Horizon disaster. It seeks to enhance offshore energy system safety and protect human health and the environment by catalyzing advances in science, practice, and capacity to generate long-term benefits for the Gulf of Mexico region and the nation.

The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. The Academies operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. For more information, visit national-academies.org.