Tag: Drug Development

Southern Research taps April Brys to lead Drug Development division

Southern Research announced today that April M. Brys, Ph.D., an experienced life sciences executive with a strong track record in research and leadership roles, has been named vice president of the non-profit organization’s Drug Development division.

Over a long and successful career, Brys has consistently achieved strategic, financial and operational goals, making her the ideal leader for Drug Development at Southern Research, according to Art Tipton, president and CEO.

“April’s strong scientific and business background brings to Southern Research the leadership we sought to continue to grow and expand our Drug Development division,” Tipton said. “Her experience will be invaluable as we seek to build new capabilities within the division while also forging new relationships and identifying new business opportunities.”

Southern Research drug development
April Brys is vice president of Drug Development at Southern Research.

Brys, whose first day at Birmingham-based Southern Research was Monday, said she looks forward to directing growth strategies for the Drug Development division, whose wide-ranging work has included evaluating bioterror threats and combatting diseases including influenza and HIV/AIDS.

“With an impressive history of exploring how to make medicines safer, improve vaccines and develop new therapeutics, Southern Research is well positioned to continue making important contributions in these areas,” Brys said.

“I am excited to join the organization and lead the effort to expand the Drug Development division’s capabilities and reach this year and beyond.”

Southern Research’s Drug Development division provides commercial and government clients with a wide variety of nonclinical and clinical trial support services. It conducts in vitro and in vivo testing of small molecule compounds, vaccines, biologics and other test articles in therapeutic areas including infectious disease, central nervous system disorders, and cancer.

Drug Development works alongside Southern Research’s Drug Discovery division to extend the Birmingham-based organization’s rich heritage of helping bring novel therapeutics to market.

Southern Research scientists have discovered seven drugs used in cancer treatments and conducted critical evaluations on a large number of medicines now being used to treat patients suffering from a sweeping range of illnesses.

LEADERSHIP ROLES

Brys joins Southern Research after nearly 19 years at Columbus, Ohio-based Battelle Memorial Institute, a global non-profit applied science and technology development organization.

For the past four years, she served as director of Battelle’s Clinical and Nonclinical Business Line, where she directed large multi-disciplinary research programs, managed key customer relationships and identified critical technology growth areas. In this role, Brys had full responsibility for a $120 million enterprise with a 350-person workforce serving both government and commercial market sectors.

During her tenure at Battelle, Brys also served as director of biomarker services and as a senior research scientist who rose to lead the Immunology Group within the organization’s biotechnology product line.

Before joining Battelle, she spent nearly five years as a postdoctoral fellow at the Robert Wood Johnson Medical School at Rutgers University in New Jersey.

Brys earned a bachelor’s degree in microbiology from Rutgers and master’s of philosophy and doctorate degrees in molecular biophysics and biochemistry from Yale University.

 

Southern Research teams with UAB to launch 3 pilot studies

How certain bacteria may make people more prone to asthma is one topic of three research grants jointly funded by Southern Research and the UAB School of Medicine.

These new research pilots are the latest effort to harness synergies between researchers at the University of Alabama at Birmingham and Southern Research, a Birmingham-based nonprofit research institute with nearly 400 scientists and engineers.

The two other pilots seek an improved way to develop new vaccines and a new mouse model for a potentially dangerous, hereditary deficiency shared by 400 million people worldwide.

The cooperation began with a July 2018 research retreat, sponsored by Art Tipton, Ph.D., president and chief executive officer of Southern Research, and Etty “Tika” Benveniste, Ph.D., senior vice dean for Basic Sciences in the UAB School of Medicine.

“While our researchers work together in many areas, we strongly suspected there would be additional ones that would be possible if both sides knew the research capabilities of each side better,” Tipton said. “And we were correct.”

“We announced at the end of it that we would fund some joint pilot programs,” Benveniste said. “Proposals were submitted and reviewed, and now three programs have been funded.”

This program parallels one held for the UAB School of Engineering, the College of Arts and Sciences, and Southern Research that was announced last July. That symposium was so successful it was repeated this month, and it will have additional funded programs to be announced later this year.

The one-year, $25,000 pilots were selected for intellectual merit, originality, potential to win major research funding and ability to foster collaborations between Southern Research and UAB.

Here are brief descriptions of the three pilots.

UAB
Javier Campos-Gómez of Southern Research and Beatriz León of UAB (Image: UAB)

ASTHMA STUDY

This study is based on the observation that human lung infections with the bacterium Pseudomonas aeruginosa are associated with more severe chronic cases of asthma and allergic sinusitis.

This suggests that the bacteria make people more susceptible to allergic airway inflammation, and that treating the lung infection could prevent severe asthma attacks. However, P.aeruginosa is often resistant to antibiotics.

The study is led by Southern Research principal investigator Javier Campos-Gómez, Ph.D., research associate biologist in the Department of Infectious Diseases, Drug Discovery Division, and UAB principal investigator Beatriz León, Ph.D., assistant professor in the Department of Microbiology

Campos-Gómez and León will investigate a different way to stymie P.aeruginosa, by probing the molecular basis for increased susceptibility to allergic inflammation and asthma in infected patients. They have preliminary evidence that a certain metabolite of P.aeruginosa may affect the immune response to allergens, and this could offer a new path to treatment therapies.

VACCINE DEVELOPMENT

UAB
Braden McFarland of UAB and Raj Kalkeri of Southern Research (Image: UAB)

This study starts with the understanding that the bacteria found in the human gastrointestinal track are necessary for the development of our immune system. However, 85 percent of bacteria found in the guts of laboratory mice are not found in the guts of humans, implying that vaccine efficacy evaluation with regular laboratory mice might not translate to humans.

The study is led by Southern Research principal investigator Raj Kalkeri, Ph.D., MBA, subject matter expert for infectious disease research in the Drug Development division, and UAB principal investigator Braden McFarland, Ph.D., instructor in the Department of Cell, Developmental and Integrative Biology.

Kalkeri and McFarland hope to bridge the knowledge gap through vaccine evaluation in humanized microbiome mice — mice that have human donor bacteria in their gastrointestinal tracts. This might be a better model to test potential human vaccine efficacy, as well as help reveal how gut microbes affect vaccine protection.

SAFETY OF THERAPEUTIC DRUGS

UAB
Babu L. Tekwani of Southern Research and Robert P. Kimberly of UAB (Image: UAB)

This study involves the hereditary condition called glucose 6-phosphate dehydrogenase, or G6PD, enzyme deficiency that affects more than 400 million people worldwide.

This enzyme deficiency can make people susceptible to drug-induced hemolytic anemia, and it can also limit use of several important drugs in public health. Yet development of safer drugs for these 400 million people has been hampered by lack of suitable experimental models for the enzyme deficiency.

The study is led by Southern Research principal investigator Babu L. Tekwani Ph.D., distinguished fellow and chair of infectious diseases in the Drug Discovery division, and UAB researchers in the Center for Clinical and Translational Science, Jennifer A. Croker, Ph.D., director of Administration, and Robert P. Kimberly, M.D., director.

Tekwani and colleagues will establish a model for the enzyme deficiency in humanized-immunocompromised mice, and then investigate the mechanism of drug-induced hemolytic anemia. This mouse model also should be useful to develop safer drug alternatives. Tekwani and his group are working on improving the safety of antimalarial drugs in populations with G6PD deficiency.

 

 

Southern Research investigates novel flu vaccine approach

The 2017-18 influenza season was brutal, with nearly 49 million Americans sickened by the flu and almost 1 million of them ending up in the hospital. The death toll was estimated at 79,400.

The most severe influenza outbreak since the 2009 global pandemic was worsened by the fact that the seasonal flu vaccine was less effective than usual. With another flu season just beginning, a question is emerging: Is there a better way to produce vaccines that will boost their overall effectiveness?

To find out, Southern Research is working to help key government health agencies explore a novel approach to creating next-generation flu vaccines that offer more protection and greater predictability.

Typically, flu vaccines are developed based on their ability to prompt the immune system to make antibodies against the most abundant protein on the surface of the influenza virus, known as hemagglutinin, or HA.

Southern Research
Southern Research is working with key government agencies on how to develop a next-generation flu vaccine that offers greater protection.

But Southern Research scientists are investigating whether a second surface protein, called neuraminidase, or NA, could also be targeted to give vaccines a higher level of protection against flu infections.

“Yes, HA is the dominant protein, but the NA actually plays a role in how the virus infects and spreads to surrounding cells,” said Landon Westfall, Ph.D., an influenza researcher in Southern Research’s Drug Development division. “If you were to block both of those, do you effectively have more of a neutralizing effect?

“We’re starting to take notice of the NA protein’s potential.”

PROVIDING PROTECTION

Usually, flu vaccines provide around 60 percent effectiveness, meaning a vaccination reduces a person’s overall risk of having to seek medical care for flu illness by 60 percent.

But in some years, the protection is less.

Last year’s vaccine was below par, with overall effectiveness estimated by the Centers for Disease Control and Prevention (CDC) to be 40 percent. Against the H3N2 virus, the predominant strain during the 2017-18 flu season, the vaccine’s effectiveness was measured at just 25 percent.

Mutations in the vaccine virus are the most likely explanation. This mutation meant that the neutralizing antibody triggered by the vaccine wouldn’t bind properly to the HA protein on the flu virus’ surface, reducing effectiveness, Westfall said.

“The vaccine is grown in eggs, and the virus that was put into the eggs was not the same virus that came out,” he said.

So far, this year’s flu season is off to slow start, with most states reporting minimal activity as of early December. Recent data, however, indicates flu levels are on the rise throughout the United States, according to the CDC’s Weekly U.S. Influenza Surveillance Report. That suggests that the vaccine is more effective this year, particularly against H1N1, the main flu strain that’s circulating in the nation.

Southern Research flu vaccine
Landon Westfall is an infectious disease scientist at Southern Research.

“As I recommend to everyone, even if the flu vaccine is not as effective as wewant, it still provides a level of protection,” Westfall said. “It’s important that everyone at least have that on board because even it if reduces the virulence of the viral infection only a little bit, it could mean the difference between life and death for some individuals.”

NEW VACCINE APPROACH

Vaccine makers have long concentrated on the HA protein in the evaluation and development of their flu vaccines. Recent research, however, has shown that anti-NA antibodies may be more important than anti-HA antibodies for protecting people from severe flu systems.

Westfall said that has important implications for vaccines, which in the future could also have an NA component.

He said Southern Research is working with government health agencies to develop an assay that can better detect anti-NA antibodies as part of a clinical trial. The goal is find a combination that leads to increased efficacy and provides greater predictability about how the vaccine will protect against certain flu strains.

“We’re trying to see if there is any type of proportional response between the proteins to see if the vaccine needs, say 75 percent HA and 25 percent NA, to reach an overall level of 65 percent protection,” Westfall said.

Birmingham-based Southern Research has been heavily involved in U.S. government influenza programs since 2004, when H5N1, or bird flu, emerged as a serious threat. Since 2009, the organization has supported the government as a primary provider of flu vaccine testing and support.

Southern Research has worked extensively on influenza projects in support of clinical trials for the National Institutes of Health (NIH), the National Institute of Allergy and Infectious Disease (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA).

 

Southern Research completes $13 million renovation of Frederick facility

FREDERICK, Maryland – Southern Research marked the completion of a $13 million renovation project at its Frederick Infectious Disease Research Center with a ribbon-cutting ceremony today attended by local leaders, state officials and research sponsors.

The project, launched after the 48,000-square-foot facility sustained damage during a torrential rain storm that struck Frederick three years ago, adds flexibility to the center’s operations and prepares it for future growth.

“Southern Research’s facility in Frederick has played an important role in advances in treatment of infectious diseases over nearly three decades, and this additional investment underscores our commitment to the groundbreaking infectious disease research being conducted here,” said Art Tipton, Ph.D, the Birmingham-based organization’s CEO and president.

Southern Research
Southern Research employees mark the completion of a $13 million rebuilding project at the Frederick Infectious Disease Research Center.

“I want to acknowledge the dedication of all of our Frederick employees during this rebuild in continued commitment to carry out important research for our customers,” he added. “The rebuild would not have been possible without the hard work of many SR employees on our facilities team both in Frederick and Birmingham.”

Infectious disease researchers at the Frederick center primarily focus on antiviral work and carry out activities such as drug and vaccine discovery and development for commercial and government clients. The center has 50 employees.

“We’ve helped pharmaceutical companies get many of their drug candidates into the clinic for trials, and the vast majority of FDA-approved antiretroviral drugs for HIV were tested in this facility,” said Roger Ptak, senior director of Infectious Disease Research for Southern Research in Frederick.

“We’ve also done a lot of significant work in developing animal models for dengue and Zika for potential vaccines against those viruses,” he added. “We have conducted pre-clinical testing on many vaccine and drug candidates here and provided support for lots of programs.”

ANTIVIRAL SCREENING

The Frederick facility, which opened in 1991, was soon handling Southern Research’s large-scale anti-HIV/AIDS screening efforts, and it made significant contributions to treatments against the disease. Today, there are more than two dozen FDA-approved AIDS antiretroviral drugs, often used in therapeutic combinations, and Southern Research was heavily involved in helping many of them get to market.

While the infectious disease research in the early days in Frederick focused on anti-HIV efforts, the center’s antiviral screening capabilities rapidly expanded to include many other viruses. These have included influenza (including the H5N1 avian flu), hepatitis B and C, dengue, anthrax, poliovirus, SARS, and Zika.

Southern Research
Southern Research CEO Art Tipton, left, poses with Ben Wu, deputy secretary and chief operating officer of the Maryland Department of Commerce, at the Frederick ribbon-cutting ceremony.

Southern Research scientists in Frederick have also developed primate models to evaluate vaccines against AIDS and anthrax, as well as other models for influenza and infections caused by monkeypox, a virus similar to smallpox.

The Maryland lab also conducts a high volume of antiviral screens against a variety of viruses for pharmaceutical companies, biotech firms, small labs, academic groups, and startups.

Rick Weldon, the president and CEO of the Frederick County Chamber of Commerce who has served in a variety of community roles, said the Southern Research lab and its employees have long been valued partners in the region.

“As the head of local United Way several years ago, I saw the passion of charity and generosity of Southern Research workers, from leadership to the lab bench to the administrative employees,” Weldon said. “Now as the Chamber CEO, I’m both grateful for the significant investment and excited to see what breakthroughs emerge from the work of the Frederick-based Southern Research team.”

STORM DAMAGE

The intense storm that pounded Frederick County on Sept. 29, 2015, dumped 5 inches of rain on the city, causing major flooding that affected local schools and wrecked the YMCA building.

Southern Research’s Frederick facility was hit hard by what was described at the time as a “100-year storm.”

Ptak said the heavy rains caused part of the roof in the rear of the structure to collapse. As part of the repair project, the back corner of the building was demolished and completely rebuilt.

“The rebuild allowed us to reconfigure and optimize the space, and we now have space to grow,” he said.

Birmingham-based HOAR Construction handled the construction project.


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SR researcher Susan Schader discusses the future of HIV treatment

Prolific, dedicated HIV researcher Susan Schader, Ph.D., believes that a cure for HIV cannot be pursued without first defining the concept of “cure.”

“There are many things that go into ‘curing,’” she said. “Are we curing the world, or are we curing the human? And that’s where I challenge the scientists I work with. You’re telling me that you’re working toward a cure? How are you curing HIV? In an individual, let’s just start there, or even a cell. Tell me how you’re curing it.”

That big-picture view—what are you working toward? What are you working for?—has largely defined Susan M. Schader’s career as a scientist. Recently promoted to principle investigator, she guides a project focused on new viral targets and novel therapeutics in the face of this constantly mutating virus. When she joined Southern Research three years ago, she immediately felt at home at the institution that has touched nearly every HIV drug that’s come to market since the epidemic began in the 1980s, turning a death sentence into a treatable disease.

Susan Schader is SR's primary investigator for HIV/AIDS.
Susan Schader is SR’s primary investigator for HIV/AIDS.

RETROSPECTIVE

Schader’s mindset goes back to her early work in the lab of Dr. Robin Shattock at St. George’s Hospital Medical School, studying the effect of TMC120 (later dapivirine) and tenofovir on HIV replication. “He was the perfect mentor. We called him the Prince of Microbicides,” Schader said. “He was always big picture-focused. Although he didn’t say, ‘Susan, you must be big picture-focused,’ he was. And you saw this side of humanity, and what you were doing in the lab meant something.”

That broad perspective would prove to be a common thread among the other mentors who had the most impact on her during her early career. Dr. John Moore, who reminded her, when she got caught up in the technical details, to “keep the big picture in mind.” Dr. Mark Wainberg, under whom she received her doctorate and who recognized her knowledge and experience and gave her the freedom to work, to lead, even to sit in his place on steering committees and at conferences—gave her a new perspective on where her work fit into the global effort against HIV.

Schader recounts a story from a visit to the International AIDS Symposium after she’d left Shattock’s lab. The TMC120 she’d been studying was in testing as part of a silicone vaginal ring that women would be able to use for protection from HIV—an important advancement for women in developing countries who might have neither access to medical treatment nor the personal agency to negotiate sexual contact.

Both researchers and workers on the front line of the AIDS epidemic attended the symposium, and it was a group of the latter, healthcare workers in Africa, who approached Schader. “They said, ‘We’ve heard about this ring. Can we see it? Can we touch it?’” she said. “And it was an aha moment for me. It’s the human connection— this is a good concept, but if you really want to get it adopted, you have to be able to say, ‘Here. Touch it. Feel it. What are your thoughts on it?’ We could have done a better job as scientists to help the people on the front lines understand where we were going. And it was those women who brought it to my attention, who said, ‘We really want this product.’”

SMALL SCALE, BIG DISCOVERIES

Over a decade later, Schader is working in a world facing a $7 billion funding gap, per the UN, between our current reality and the goal of eradicating HIV by 2030. “That to me just says, it’s got to stop being about a country,” she said. “It’s got to stop being about the person. You can treat an individual, but we also have to look longer term.”

“What I can do in the lab is on a very small scale,” Schader said. “But I know by bringing everyone together at Southern Research, it’s the biggest
gift I’ve ever been given in my career, because the scientists I work with have the capacity to do what no other research lab can do or would attempt. The scientists here are dedicated, and they want to stay here. I learn something new every day here, and we’ve already discovered things that, hopefully by the end of the year, we can get some funding to help us carry on research.”

Schader believes the biggest thing standing between science and a cure—a cure by any definition—is funding. A constant struggle for a share of limited grant money pits scientists against each other, she said, and impedes collaboration. That, combined with lack of access to new technology, resources and brainpower, hinders potential advances.

Teams have had to innovate new technology using their own research funds, or just go without. “Struggling for two days with something when you can buy a piece of equipment that will let you do it in 30 seconds or less—just those processes can make us less frustrated and more productive,” she said. “What we’ve accomplished over the past year, we could have accomplished a lot faster.”

Those accomplishments are significant. What other labs are unable to do, Schader’s team specializes in doing—developing ways to detect HIV in active replication, to test drugs, to design novel, clinically relevant assays. Her lab is the first in the world to produce protein from HIV in a particular bacteria. That discovery can mean the difference between the therapies that were effective decades ago and the ones that are changing the world now. “We just need the funding to be able to sit down and say, ‘OK, let’s work together.’”

THE BIG PICTURE, FULL CIRCLE

While her team works toward the future, a project from Schader’s past has reappeared. While pursuing her doctorate, Schader was awarded nearly a quarter of a million dollars from the International Partnership of Microbicides to study the drugs they wanted to test in combination—research that led to the silicone ring that had made waves at the IAS. Now, she’s been approached directly—this time to supply preclinical data because the dapivirine ring is a reality, has been tested in Africa and is up for regulatory approval in Europe. “I was involved at the beginning, and now I get to see and help bring it to people under the European regulatory agency,” she said. “And it’s at Southern Research that we’re doing it.”

Seeing it come full circle isn’t just a thrill for Schader—it’s also educational and encouraging for her team, she said. “To actually say we’re helping women on a worldwide scale, it really makes people look up from their bench and go, ‘Yeah, what I do means something.’”

“I think we can do it,” Schader said. “I think we can cure HIV. We just need to know what a cure looks like.”

Southern Research programs aim to shield against pandemic flu dangers

With experts predicting another deadly influenza pandemic in the future, Southern Research scientists are working on several fronts to help limit the death toll from a catastrophic flu outbreak that one day slams the nation.

Birmingham-based Southern Research conducts tests on emerging pandemic strains and participates in strategic government vaccine programs focusing on highly pathogenic avian influenza (HPAI) strains that pose potentially grave public health risks.

In addition, Southern Research has performed toxicology studies for flu vaccine platforms and provided pre-clinical studies on vaccine candidates, along with clinical trial support for vaccine makers. The non-profit organization has also researched antiviral treatment approaches that could protect people after infection.

“Scientists will tell you it’s not if, it’s when we have a pandemic. That’s the way the flu virus works,” said Landon Westfall, Ph.D., a senior project manager and infectious disease scientist at Southern Research. “It’s like the San Andreas fault – the big one is coming one day. The idea is since we can’t prevent it, we should prepare for it. That’s the goal.”

pandemic influenza Southern Research
The last global flu pandemic, the 2009 H1N1 swine flu outbreak, killed as many as 575,000 people across the globe.

Pandemic influenza strains pose much a greater threat than even the nastiest strains of seasonal flu. The dominant seasonal strain this year, H3N2*, fits that description, causing an above-average rate of hospitalizations and prompting Alabama to declare a public health emergency.

The current flu season’s misery is worsened by the fact that the available vaccine is only moderately effective.

“That’s the challenge with flu. Vaccines don’t always work,” Westfall said. “Most of the time, they protect 55 to 60 percent of the population. That’s kind of the goal of influenza vaccines. But there will always be subsets of the population that won’t be protected.”

ELEVATED DANGERS

Novel avian or swine flu strains, however, have the potential to cause lethal damage on a global scale. Because these dreaded strains are new, very few people have immunity against them, so they can spread widely and rapidly, sickening a large segment of the population, Westfall said.

When pandemics emerge, more than half of an affected population can be infected in a single year, while the number of deaths stemming from the flu outbreak can sharply exceed normal levels.

That’s why the work being conducted by Southern Research and other organizations as part of the U.S. government’s influenza preparedness programs is critically important, Westfall said.

The goal is to prevent a global calamity like the 1918 Spanish flu pandemic, which killed more than 50 million people, and outbreaks in 1957 and 1968 that each killed at least 1 million people worldwide. The last pandemic, the 2009 H1N1 swine flu outbreak, killed as many as 575,000 people. More information on pandemics.

pandemic flu Southern Research
Landon Westfall is a senior project manager and infectious disease scientist at Southern Research.

For more than a decade, pandemic fears have centered on the highly lethal H5N1 avian influenza, despite the fact that the so-called “bird flu” virus does not infect humans easily. If a mutated form of the H5N1 virus became easily transmissible from person to person while retaining its severe effects, the public health consequences could be very serious, the World Health Organization warns.

“For the most part, avian influenza affects birds. When the virus makes a jump for one species to another, say from bird to human, that’s a big thing,” said Westfall, who oversees the influenza virology program for Southern Research’s Drug Development division. “That’s a rapid evolution for a virus that will likely cause major problems. In cases, where the avian flu has infected humans, the mortality rate has been around 60 percent.”

Southern Research scientists have worked on influenza projects for government agencies including the National Institutes of Health, the National Institute of Allergies and Infectious Diseases, and the Biomedical Advanced Research and Development Authority. The organization has also worked with a number of commercial clients.

“We’re recognized as one of the leading supporters for clinical vaccine research, especially for flu,” Westfall said. “That is partly because of our history in the field but also because of our capabilities to test a large volume of samples in a relatively short time.”

THE NEXT PANDEMIC

Southern Research flu pandemic
The H1N1 virus triggered a global influenza pandemic in 2009.

Although most experts believe another influenza pandemic is inevitable, Westfall said it is impossible to predict when or where it will occur, or how severe its impact will be. It’s almost impossible to predict with certainty the subtype of influenza virus most likely to cause the next worldwide outbreak.

Late in 2017, scientists reported that a new strain of H7N9 avian flu circulating in China showed the ability to transmit easily among animals with highly lethal results, raising alarm about its potential to trigger a global human pandemic.

While the Centers for Disease Control and Prevention says the risk of H7N9 is currently low because human-to-human transmission is rare, the CDC still rates the strain as having the greatest potential to cause a pandemic.

Westfall said the evolving nature of influenza viruses presents tough challenges to the research community.

“Flu is like a malleable pathogen that can change from week to week, from month to month, and from region to region,” he said. “Every person who gets infected with the flu basically creates a small change in that virus that’s then passed on to multiple people. Flu constantly changes that way.”

*In the designation of influenza subtypes, the H refers to hemagglutinin, a protein found on the surface of flu viruses, while the N refers to viral neuraminidase, another protein present on the surface of the virus.


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Researcher developing new toxicology test to protect unborn children

Southern Research reproductive toxicology scientist Paul Bushdid, Ph.D., is working to develop a new, cost-efficient laboratory test to evaluate hazards to unborn children posed by potential medicines, chemicals and other agents.

Bushdid’s in vitro toxicology model, based on a chicken embryo, promises to deliver significant benefits. For one thing, the model should produce more rapid hazard assessments of potential threats to a developing fetus. In addition, the model could help trim the costs of drug development projects, he said.

“This in vitro model should give us the ability to assess a lot more compounds and agents at a reduced cost, with reduced animal use, and we should be able to do it faster,” said Bushdid, who is director of the Drug Development division’s Toxicology & Pathology Services and discipline leader for the Developmental & Reproductive Toxicology (DART) program.

Southern Research’s Paul Bushdid, center, and his team are developing a new in vitro toxicology test based on a chicken embryo.

Southern Research’s DART program performs complex preclinical studies to ensure that drug candidates, nutritional supplements, food additives and chemicals don’t endanger unborn children and pregnant women. It also examines whether these substances are negatively affecting fertility in men and women.

Bushdid said in vitro models are gaining momentum in toxicology, which provides scientific analysis of potentially hazardous chemicals and investigates the toxic properties of new substances being used in consumer products and industrial settings.

“If there are ways other than animal studies to get results – in vitro models of toxicity being one of them – we should pursue them,” he said.

CREATING A ‘POWERFUL SCREEN’

Bushdid’s project, funded internally at Southern Research, aims to significantly update and improve an older laboratory technique that was widely used in reproductive toxicology tests until the 1980s. That’s when concerns emerged about whether the chicken embryo model was the best platform for assessing teratogens, or agents that cause malformations in an embryo.

“It fell out of favor because the chicken doesn’t have a placenta, but the data shows that if you are looking at a direct teratogenic assault on an embryo, that chicken embryo model is a great model, with a high degree of predictability of what happens in humans,” Bushdid said.

To improve the in vitro model, Bushdid plans to add other assessments that have not been standard for the assay but have proved useful in animal models. Combining the two will make “a very powerful screen for assessments,” he said.

“With the chicken embryo, we can look at a very wide range of developmental stages, and we can identify potential target organs. It’s important to know if the agent in question is perfectly safe or has the potential to be lethal or cause limb defects like thalidomide did,” Bushdid said.

“That will help provide guidance on what type of further testing is needed to ensure safety for people.”

Paul Bushdid is director of the Drug Development division’s Toxicology & Pathology Services and discipline leader for the Developmental & Reproductive Toxicology (DART) program.

Bushdid believes the in vitro toxicology model could help hold down costs in drug discovery and development programs, which face significant financial hurdles in getting a medicine to market.

“Drug development is extremely expensive, and the cost of that eventually gets relayed to the public,” he said. “How can we help with that? Well, we can work to develop and validate alternate models for safety assessment to help reduce the overall cost of drug development.”

IMPORTANT PROTECTION

Southern Research’s DART program is a key partner of the National Toxicology Program, which is responsible for evaluating the toxic and carcinogenic potential of environmental agents that may pose a health hazard to U.S. citizens.

The NTP is affiliated with the National Institute of Environmental Health Sciences (NIEHS), which awarded Southern Research a 10-year contract to evaluate the long-term effects of early-life exposure to certain chemicals. The NIEHS is part of the National Institutes of Health.

“It’s been my personal goal in life to protect kids, before they’re born or after they’re born,” Bushdid said. “To me, children are sacred in a world that is full of dangers. The whole purpose of everything we’re doing is to make sure they are protected.”

Southern Research targets bio-threats under BARDA contracts

Southern Research has been awarded two contracts from the Biomedical Advanced Research and Development Authority (BARDA), which is a division of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response, for nonclinical research services advancing the agency’s work to protect the U.S. against infectious disease and bio-terror threats.

The BARDA contracts have a minimum value of $45 million and a maximum value of $90 million and a base term of five years.

Southern Research, which has considerable experience in infectious disease research, has long been a leader in the evaluation of vaccine candidates and possible therapeutics for influenza and emerging biological threats.

Southern Research bio-threats
Southern Research has won two contracts from BARDA for work to protect the U.S. from infectious diseases and bio-terror threats.

“This work positions Southern Research to play a key role in protecting against potentially serious public health issues,” said Tim McGrath, vice president, Drug Development.

“We have the expertise and capabilities to accelerate the development of vaccines and therapeutics that are effective against biological threat agents.”

PORTFOLIO OF COUNTERMEASURES

BARDA’s mission includes developing medical countermeasures our nation needs to protect public health against emerging infectious diseases, pandemic influenza, and chemical, biological, radiological, and nuclear threats.

Under one of the BARDA contracts, Southern Research will develop and utilize novel animal models used in the testing of potential vaccines and therapeutics against biological threat agents.

The development of animal models is considered a key element in the evaluation of medical countermeasures for this broad range of threats because the efficacy of these products cannot be verified using traditional clinical studies.

“Southern Research is pleased to continue this relationship with BARDA and support this critically important initiative,” said Michelle Wright Valderas, director of project management and principal investigator on this contract.

The second BARDA-supported project is focused on developing the reagents and assays that would be used to support the animal model testing and later human clinical trials.

“I am excited to contribute to this important research supporting vaccine development to protect public health,” said John Farmer, a project leader responsible for immunology research at Southern Research and principal investigator on this contract.

IDIQ CONTRACTS

Task orders issued under these contracts will be funded in whole or in part with federal funds from the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under Contract Nos. HHSO100201700017I and HHSO100201700018I.

Both are Indefinite Delivery Indefinite Quantity (IDIQ) contracts, meaning Southern Research is positioned to bid on task orders once they are issued by BARDA. All work will be conducted using quality standards consistent with Good Laboratory Practices (GLP) guidelines.

Southern Research worked previously with BARDA under a 2011 IDIQ contract to develop animal models. In addition, Southern Research has worked as a subcontractor with other organizations on BARDA contracts.

Southern Research ready to assist new hepatitis B treatment approaches

A Southern Research scientist says a new generation of antiviral therapies is urgently needed against hepatitis B, a chronic disease affecting 240 million people whose cure has proved elusive.

Raj Kalkeri, Ph.D., a project leader and subject matter expert in infectious disease for Southern Research’s Drug Development division, added that the stubborn characteristics of the hepatitis B virus (HBV) have thrown up significant hurdles slowing the discovery and development of a cure for this persistent viral infection.

“Because of its role in at least 650,000 deaths each year, hepatitis B constitutes a major international public health problem,” Kalkeri said. “HBV persistence can lead to cirrhosis, liver failure and the primary form of liver cancer, hepatocellular carcinoma. This places a major burden on health care costs.”

Southern Research hepatitis B
Raj Kalkeri, standing at right, works with a HBV team in a Southern Research laboratory.

Birmingham-based Southern Research has been active in the effort to advance new treatments by developing comprehensive hepatitis B capabilities for researchers. This includes in vitro assays to monitor different phases of the HBV life cycle, along with a mouse model for persistent HBV infection that could be useful in testing a new generation of HBV therapies.

What’s needed now, Kalkeri said, is greater cooperation within the scientific community and additional support for research that targets the infection’s most challenging aspects, including its persistence and ability to suppress an immune system response.

“Concerted efforts across academia, industry and government are needed,” he said. “Collaborations across these groups with additional research funding will facilitate better understanding of HBV persistence and the development of effective strategies to advance a functional cure.”

COMBATTING PERSISTENCE

While there is a safe and effective vaccine for hepatitis B, it fails in 5 to 15 percent of persons receiving the vaccine. Smoking, obesity, other chronic illnesses and advanced age are some of the factors associated with vaccine failure.

Current antiviral therapies can halt the progress of the infection in some patients, but they don’t wipe out all traces of the virus. That allows HBV to hide out for some time, before reappearing once therapy is completed.

Hepatitis B’s persistence, which can turn the disease into a lifelong struggle for many sufferers, is a complex phenomenon, Kalkeri said.

For starters, the human immune system has a hard time clearing out hepatitis B. It begins when T-lymphocytes, a key component of the immune system that combats microbial intruders, fail to do their job because of disruption caused by the virus.

Reversing this defective T-cell response could be helpful in the development of new hepatitis B treatments, though it’s probably not sufficient alone to play a starring role in a cure, Kalkeri said.

The major challenge with hepatitis B persistence is known as cccDNA, short for covalently closed circular DNA. This is a special DNA structure that’s deposited in the nucleus of HBV infected cells in the form of minichromosome. Its strategic location makes it a difficult target for antivirals and for the immune system.

Present in low levels, the seemingly untouchable cccDNA continues to produce the virus even in patients being actively treated.

“As a result of the persistence of cccDNA, antiviral therapies now have to administered lifelong for a majority of HBV patients in order to avoid a reactivation of the virus,” Kalkeri said.

“The bottom line is that long-term therapy is ineffective in eliminating HBV from infected patients and results in drug toxicity issues, as well as the emergence of viral resistance,” he added.

REASONS FOR OPTIMISM

While there are promising signs that hepatitis B research is making progress, the persistence problem may ultimately put a final cure out of reach, Kalkeri said. What could emerge, however, is a way to control the disease’s persistence, resulting a functional cure, he added.

“It’s more realistic to hope for a functional cure for HBV, which means viral replication would be suppressed and other functions would be restored to a normal level,” Kalkeri added.

One source of optimism revolves around the discovery that a cell surface protein known as NTCP acts a receptor for hepatitis B. In essence, NTCP opens the door for the virus to enter into healthy cells.

“With the discovery of NTCP, we could potentially use it as a tool in the laboratory to understand the mechanisms of HBV infection, cccDNA formation, and more,” Kalkeri said.

“At a minimum, this kind of infectious cell culture model would enable identification of HBV entry inhibitors and pave the way for combination studies along with other antiviral agents against this infection.”

Kalkeri said Southern Research’s HBV cure assay capabilities are available to advance research. These testing platforms are:

IN VITRO

Virus yield assay (HepG2.2.2.15 cells)

Infectious virus assay (HepG2-NTCP)

HBV core promoter assay

Inducible HBV cccDNA model (HepDE19)

IN VIVO

Adeno-Associated Virus-HBV mouse model (C57BL/6)

Using the tools developed for the HBV program and in collaboration with Southern Research’s Drug Discovery division, Kalkeri and his team have demonstrated the inhibition of HBV core promoter by a repurposed anti-cancer clinical candidate SRI-032007. The research shows that it is feasible to reduce the production of the viral genetic material in an in vitro laboratory setting. This work is being presented as a poster in September at the 2017 International HBV meeting in Washington, D.C. Additional testing in animal models of this compound is being planned. Finding new antivirals for HBV could complement the anti-HBV activity of current and help in the development of effective curative strategies.

Read an article on HBV by Kalkeri in Future Virology.

Southern Research probe of Zika looks into ‘rebound virus’

Southern Research scientists are investigating how the Zika virus is able to find a safe harbor in an infected host’s tissue and stage a rebound weeks after the virus was seemingly cleared by the immune system.

Evidence of a Zika virus rebound, called a “secondary peak” following an initial infection, emerged during a Southern Research-funded project to determine how the virus progresses in infected cynomolgus macaques.

In that study, researchers found an ever increasing presence of viral RNA, a scientific marker for the presence of the virus itself, in the testes of monkeys. Prolonged shedding of the virus was also detected in urine.

“We hypothesized that the Zika virus is using the immune privileged tissue as a reservoir and going dormant, or in low replication mode, just hiding there,” said Fusataka Koide, associate director of infectious disease research at Southern Research.

Koide and fellow SR staff, Laurie Queen and Priscilla Williams, view a viral titer plate to determine if a drug presents the growth of Zika virus.
Koide and fellow SR staff, Laurie Queen and Priscilla Williams, view a viral titer plate to determine if a drug prevents the growth of Zika virus.

“When the immune status changes in the host, the virus could surge again,” he added. “An adaptive mutation and selection process post-infection could also contribute to successful establishment of Zika virus in a host.”

While a deeper understanding of this Zika virus rebound is needed, a possible mutation-driven secondary peak of the virus could pose new challenges for companies attempting to develop anti-viral therapeutics for post-infection treatment.

“They’ll need to study the mechanism of how the infection occurs to come up with an effective strategy for the drug,” Koide said. “Maybe it will prevent the initial viremia, but it could come back later on. They’ll need to know the drug can penetrate those tissues that may be harboring Zika virus.”

MEETING AN URGENT NEED

Zika virus infection exploded as a global health threat in early 2016. Since then, Southern Research has been heavily involved in the scientific community’s efforts to better understand the virus’s pathogenicity and has assumed a leadership role in providing efficacy models for evaluation of potential vaccines and anti-viral treatments.

Last year, the National Institute for Allergies and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH), contracted Southern Research to develop a non-human primate model for evaluation of candidate novel therapeutics and vaccines for protection and control of Zika virus infection.

Koide said potential vaccines are now being tested in macaques, with promising results in a proof-of-concept study that demonstrated that an immune system response had been triggered against the virus. In August, he said, efficacy studies will begin with potential new anti-viral compounds.

In addition to non-clinical research, Southern Research is now providing Phase-I clinical trial support for pharmaceutical companies that are working to develop vaccines against the Zika virus, Koide said.

While fears about Zika virus infection have somewhat faded since last summer, Koide said that it remains a threat and there is still an urgent need for both an effective vaccine and anti-viral treatments.

Last year’s outbreak of the virus in Brazil and South and Central America led to a significant increase in the number of children born with microcephaly, or an unusually small head. Cases of Guillain-Barré Syndrome and other neurological disorders were also reported.

“Vaccines are a preventative measure, which is probably the most effective strategy to fight Zika virus infection,” Koide said. “But some populations — pregnant women, the elderly, and immune-compromised individuals — may not be able to receive a vaccine and will need to rely on anti-viral drugs for protection.

“That’s important. You need both arms – vaccines and anti-viral drugs to fight the virus,” he added.

What you need to know about Zika virus transmission.

 

Researchers viewing the device counting the number of areas on the plate where the Zika virus is replicating.
Researchers viewing the device counting the number of areas on the plate where the Zika virus is replicating.

REBOUND RISKS

Meanwhile, Southern Research scientists are also working to completely understand the Zika virus’s ability to stage a rebound. Just how does the virus manage to survive in a host after an initial onslaught by the immune system appears to eliminate it?

To study the escape process, they’ve isolated the virus from the first acute infection phase, and later, from the secondary peak, so they can examine genetic differences between the two viral populations in order to determine if specific changes in RNA sequence might be associated with the rebound.

This kind of rebound is not seen in similar viral diseases such as Dengue fever, making Zika virus unique, Koide said.

“We just don’t know what triggers the rebound,” he added. “That is something we need to tease out because it’s RNA we’re detecting, not an infectious particle per se. Studying Zika virus’s ability to persist in immune privileged tissues (such as testes) could have important implications for non-vector mediated transmission of Zika virus.”

And while the rebound virus is eventually cleared by the macaques, Koide said revealing the Zika virus’s safe harbors is critical to evaluating whether there’s a risk that the rebound could change how the infection progresses in humans, either through enhanced transmission or potentially escalating clinical complications.

“Understanding the role viral reservoirs play in Zika virus’s immune escape should provide strategic insights for the development of new vaccines and therapeutics,” Koide said.