Tag: Drug Development

Southern Research targets bio-threats under BARDA contracts

Posted on August 8, 2017

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

Posted on July 28, 2017

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’

Posted on June 21, 2017

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.

Helping clients with Immuno-Oncology research

Posted on March 27, 2017

Since Southern Research received its first contributions for cancer research in 1946, our scientists have been working independently and with U.S. government and commercial clients to understand and work toward cures for various cancers. During the organization’s 71-year history fighting this devastating disease, Southern Research has endeavored to stay on the front of this challenge. This commitment has led to the development of the first quantitative tumor models, the log-kill model, combination chemotherapy, and the discovery of seven approved chemotherapeutic drugs. Our Drug Development team has built a well-established reputation as a pioneer in anticancer drug development, having evaluated half of all FDA-approved anticancer drugs currently on the market. And we continue to evaluate hundreds more compounds annually to establish the in vitro biochemical effects and in vivo efficacy of potential new anticancer drugs.

The world’s “newest” tool helping to eliminate cancer is the human immune system. Southern Research is committed to helping clients working in the Immuno-Oncology realm the same way we have helped the cancer research community for the past seven decades. The first of our Immunology-Oncology models was presented at the 2016 Immuno-Oncology Summit in Boston. Since then, our efforts have continued. If you plan to attend the upcoming American Association for Cancer Research in Washington, D.C., our drug development scientists will be waiting to talk with you at the Southern Research booth, #2423, about our anticancer efficacy services.

 

Internship program offers research experience, attracts bright minds to science

Posted on January 27, 2017

College students from across the U.S. are getting firsthand experience with the innovative work conducted at Southern Research in the latest generation of the nonprofit’s internship program.

Interns from Princeton University, Emory University, the University of Virginia, Birmingham-Southern College, the University of Alabama, and the University of Alabama at Birmingham (UAB) are among those who have participated and gained experience similar to that found in potential future careers.

Southern Research internship
Daniel Unger, a UAB senior majoring in chemistry and neuroscience, is working with a Southern Research team to develop a small molecule target for anti-HIV drugs.

The internship program within each department at Southern Research (SR) offers different opportunities. In general, most students do research for course credits. During the summer months, SR has paid interns which allows the students to gain additional experience outside of the classroom.

Southern Research has had various internship programs, but the newest program was initiated by Corinne Augelli-Szafran, Ph.D., director of the Chemistry Department in the Drug Discovery division.

“The intern program at SR is an excellent opportunity for the students to get hands-on experience in a laboratory. In addition to having the students exposed to a drug discovery environment, this program contributes to the Chemistry Department while reaching out to the community,” she said. “This type of program is good for everyone involved.”

In the Chemistry Department, a team of more than 25 chemists works on various research programs, including those involving treatments for Lou Gehrig’s disease (amyotrophic lateral sclerosis), Parkinson’s disease, Alzheimer’s disease, tuberculosis, kidney disease, HIV, and a wide range of cancers. The department is responsible for the preparation of potential new chemicals that will become drugs.

INITIATING A PROGRAM

Augelli-Szafran’s career in drug discovery research spans 30 years, with stints at Harvard Medical School, Parke-Davis, and Pfizer. At both of the big pharma firms, there were internship programs that drew students from neighboring universities into the workplace. At Harvard, she initiated a student internship program similar to the one she initiated at Southern Research.

When she came to SR, there was no such program in place at the time. What resulted in the Chemistry Department, is a program where students can earn course credits. Throughout the term, the students work with a mentor and do a presentation or write a research report at the end of the term.

Southern Research internship
Intern Katie Russell, a junior chemistry major at Birmingham-Southern College, is considering a career in drug discovery research.

“It’s been over a year now since we started the program, and we’ve had seven students come through in Chemistry,” she said. “They work in the lab, they do chemistry reactions, they make compounds, isolate them, purify them and characterize them – the same things a chemist would do.”

During their time in the program, if students are able to make a few compounds to be tested, it’s a major accomplishment, Augelli-Szafran added.

“It’s a great experience to learn how to do the chemistry. It’s just great exposure, and it can sometimes help the students decide what to do after undergraduate studies, whether to pursue further education or seek a job in a certain specialty.”

LAB EXPERIENCE

For the Drug Development division, the nine interns who worked there last summer served a great need, said Sarah Ziegler, Ph.D., biosafety program and compliance manager.

The group mainly worked on biosafety issues – keeping workers safe and regulatory compliance – in the division that is focused on taking pharmaceuticals and equipment to market and all that entails. The Drug Development division is responsible for a wide range of testing activities.

Out of the nine interns, Southern Research hired three for full-time positions after their internships were over.

“It was a way for us to get in help, but they also had a great perspective in a more innovative way,” Ziegler said. “They were mostly focused on biosafety and working with us on inventorying samples. They also did paperwork for us and lab cleanup. It was not necessarily the most fascinating work, but it was definitely very helpful for us.”

For the interns, the experience offered real-world work experience in a lab setting, she said.

“They actually had a lab they were in charge of, so they were understanding how to function in that arena. Their projects spanned the whole Southside campus. They interacted with people from Drug Discovery and Drug Development, and they met researchers in every lab.”

Part of the program involved a weekly lunch and learn where Ziegler invited interns from across the campus to hear from Southern Research scientists and other professionals.

“We had people talk about quality, human resources, Zika, influenza and more. It was really interesting, and I even learned things about my organization I didn’t know,” Ziegler said.

EXPLORING CAREERS

Southern Research internship
Abigail Holt, a sophomore chemistry major at Birmingham-Southern College, is interning at Southern Research.

Interns working in the Drug Discovery division say the experience they have gained is invaluable.

Birmingham-Southern College students Katie Russell and Abigail Holt are both interning at SR during the month of January to explore their future career and education paths.

Russell, a junior chemistry major, is learning organic synthesis techniques and how to analyze structure and purification data. She is an intern for postdoctoral researcher Shilpa Dutta, Ph.D., who is working on small molecule inhibitors for cancer therapeutics.

“I’m interested in the drug discovery career path, and I want to go to grad school,” Russell said. “I’ve done research work for one of my professors at Birmingham Southern, and I wanted to see how the process varies in an industry setting.”

Holt, a sophomore chemistry major, said she’s always been interested in pharmaceuticals and she’s trying to decide whether she wants to work as a researcher for a large firm.

“I think I’m really learning the most about day-to-day life and how professional chemists do their jobs instead of just being in a lab with a bunch of my classmates,” she said. “Even if I don’t end up becoming a researcher at a big pharmaceutical company, this internship has been really helpful in figuring out what I want to do. I’m glad I had the opportunity.”

UAB seniors Jaden Cowan and Daniel Unger are in the middle of longer internships. Cowan has been with Southern Research since last May, while Unger joined in August.

Southern Research internship
UAB senior Jaden Cowen, a chemistry major, is working on creating compounds for a potential anti-viral drug as part of his Southern Research internship.

Cowan, a chemistry major, initially did the internship for school credit, and he liked it so much he signed up for another semester to do his senior thesis. The thesis is on the work he’s done so far, which is creating compounds that could be used in an anti-viral drug.

His ultimate goal is to become a research scientist. During his time at SR, he has set up experiments, monitored those, run tests on the compounds, and analyzed the results.

“Since I’ve been here, I’ve decided I’m going to try to obtain a Ph.D. in chemistry, and all these skills I’ve learned so far during this internship are going to be directly used in graduate school,” Cowan said. “This is good experience working in a professional lab alongside professional researchers. They’re prepping me so I can be independent and work in a lab by myself later on.”

Unger, a chemistry and neuroscience major, joined Southern Research after reconsidering his career plans.

“I added my chemistry major in the spring of last year, after I decided to look into career options other than medicine. I came the realization that I really enjoyed teaching,” he said. “So I decided to get a Ph.D. in chemistry, and I needed hands-on experience in the lab.”

Currently, Unger is working with a team on a project to develop a small molecule inhibitor as an anti-HIV therapy, a compound that essentially stops the virus from being able to replicate itself.

He sets up reactions on his own, as guided by his research mentor, and he follows the reactions, checking to see when they are completed. He also isolates and characterizes products from various reactions.

“It’s absolutely been beneficial, and I feel I’ve learned a lot. I have a much better grasp on what’s involved in doing the work as I prepare for grad school,” Unger said.

ATTRACTING TALENT

Dr. Bo Xu, MD, Ph.D., distinguished fellow and chair of the Oncology Department, said the internship program helps Southern Research attract more talented people to join the nonprofit.

Xu notes SR’s long and storied history when it comes to cancer research, which dates to the 1940s and includes more than $90 million in grant funding from the National Institutes of Health alone.

“It is part of our mission that we want to attract more talented people to join us, to be future scientists,” he said. “We want to see them get involved and engaged in the early stages of their career and training.”

Interns in the Oncology Department typically are assigned a small project, as well as a mentor who provides hands-on training. They’re taught how to design an experiment, analyze the data, write a report and present it to the entire department at the end of the term.

The subject matter the interns are studying is the cutting edge of cancer research, Xu said.

For example, this year a student from UVA shadowed a Southern Research scientist and learned about immunology/oncology research, specifically how to culture lymphocytes and how to design experiments for potential treatments.

“Basically we are having more young people come and learn and understand what science is, what cancer research is and how cancer research can help people,” he said.

National Cancer Institute awards major contract to Southern Research

Posted on November 28, 2016

Southern Research has been awarded a new, five-year Indefinite-Delivery Indefinite-Quantity (IDIQ) contract from the National Cancer Institute to investigate the pharmacokinetic properties of antitumor and other therapeutic agents of interest to the Division of Cancer Treatment and Diagnosis (DCTD) under NCI contract HHSN261201600021I.

Southern Research NCI contract
Bernard Ntsikoussalabongui and Katie Isbell of the Drug Development division study results in a Southern Research lab.

RFP number N02CM67000-11 was issued under full and open competition, which resulted in five IDIQ awards. Task orders will be competed among the five IDIQ Contractors in the award pool and placed off of the IDIQ as requirements arise.

This IDIQ contract is one of three long-term contracts the Birmingham-based organization holds with the NCI to support its objective of developing compounds against cancer and other diseases.

“Southern Research has been working with the NCI for over 30 years with one goal in mind: helping advance the pipeline of potential drug candidates so the NCI can move forward with clinical trials,” said Sheila Grimes, D.V.M., Ph.D., D.A.C.V.P., pathology program leader and principal investigator on the project for Southern Research.

KEY ANALYSIS

Pharmacological testing is an integral part of the drug discovery and drug development processes. In order for clinical trials to commence with a candidate compound, researchers must first answer questions pertaining to how the drug interacts with, and exists within, the human body.

To accomplish this goal, Southern Research will employ a number of tests to explore in vivo tumor models and analyze the bioanalytic makeup of the compound. Under the scope of the contract, the organization is tasked with evaluating how the sample drug moves through a living system and analyzing the amount of time required for candidate compounds to break down within a system, or under a range of conditions.

“Southern Research has worked closely with the NCI for more than 30 years, and we are proud to continue those efforts in this program defining the pharmacokinetics of the next generation of anticancer medications,” said Art Tipton, Ph.D., president and CEO of Southern Research.

“The trinity of government, industry, and nonprofit research organizations like Southern Research is a necessary collaboration to enable most drugs to reach the market. We’re pleased to continue our role, and I commend our team for their ongoing extraordinary work in the field.”

NIH orders High Throughput Screening for Zika

Posted on November 7, 2016
High Throughput Screening for Zika
Working with assays in Sourthern Research’s High Throughput Screening lab.

In 2014, Southern Research received funding from the National Institute of Allergies and Infectious Diseases (NIAID) through a multi-center U19 grant (U19AI109680) administered by the University of Alabama at Birmingham to conduct high throughput screening (HTS) against six disease-causing viruses: dengue, West Nile, SARS, influenza, Venezuela equine encephalitis complex, and chikungunya. With the program in place, and as Southern Research has completed screening the viruses, the National Institutes of Health (NIH) issued a supplementary $650,000 award for the Birmingham-organization to expand its program to include high throughput screening for Zika.

“Southern Research has a long history in antiviral research, including screening viruses in the same flavivirus genus as Zika, so we’re pleased the NIH saw fit to expand the U19 program to include screening on Zika,” said Bob Bostwick, Ph.D., director of the High-Throughput Screening Center at Southern Research. “For drug discovery purposes, we hope to identify compounds that work well across this entire genus.”

According to the supplemental grant, Southern Research will construct an assay for Zika that can be conducted in HTS, and test over 300,000 compounds against the virus, a process that will take nine months.

Developing robust screening capabilities

For Southern Research, compound screening has been a part of the organization’s efforts since the mid-1950s, when researchers began manually screening anticancer drugs under a contract with the National Cancer Institute (NCI). Around this same period, the Virus Research Division began evaluating antiviral agents against a wide range of pathogenic viruses, including the herpesviruses, poxviruses, acute upper respiratory disease viruses, and mosquito-borne viruses, such as Yellow Fever virus.

By the 1960s, the early work had already shown promise. Manual screenings conducted by the viral research team had identified the compounds that led to the discovery of Ara-A, an antiviral used to treat human herpesviruses, chicken pox, shingles, human cytomegalovirus — a cause of childhood hearing loss — and a lethal encephalitis.

In the 1980s, following the emergence of the AIDS epidemic in the United States, Southern Research expanded into HIV antiviral research through a series of contracts and grants with the United States Army and the NIH. This effort involved screening compound collections consisting of approximately 20,000 samples, and developing a staff of scientists proficient in working with many infectious diseases. By the following decade, the organization’s anti-HIV screening program had become the largest in the country.

While earning a global reputation for producing high quality antiviral research, Southern Research’s screening capabilities were expanding far beyond antivirals to include screening of other infectious diseases and cancer. In the late 1990s, the organization invested in emerging HTS technologies to maintain a prominent role at the forefront of drug discovery. This involved assembling a large compound collection — consisting of over 1 million samples — and acquiring robotic platforms for automated screening, thus enabling the organization to test hundreds of thousands of compounds for each new target. Eventually, the program would become involved in the NIH Roadmap Molecular Libraries initiative, and serve as one of twelve centers in the NCI Chemical Biology Consortium.

“Southern Research’s in-house screening capabilities are unmatched by most universities and private research organizations across the globe,” said Art Tipton, Ph.D., president and CEO of Southern Research. “With our Biosafety Level 3 (BSL3) facility, an active in-house library of over one million compounds, and a wealth of institutional knowledge, our researchers pride themselves on finding chemical structures needed to develop drugs against some of the greatest global health threats.”

High Throughput Screening and drug discovery

Zika Virus
Zika Virus under high magnification.

Today, HTS is an automated process that allows researchers to rapidly test a large number of compounds in order to determine their potential use as starting points for the invention of new drugs. With time and advances in technology, the process of screening compounds has evolved significantly from the early days. However, despite these advances, some things remain the same.

“Whether you are working on an antiviral or an anti-cancer medication, the drug discovery process is incredibly complex and often starts with screening,” said Bostwick. “HTS usually requires screening hundreds of thousands of compounds to find three or four good chemical starting points for medicinal chemistry.”

With the recent expansion of its U19 program to include screening of the Zika virus, Southern Research maintains a prominent global position in antiviral research. Its work has led to the fight against HIV/AIDS — supporting the United States government and numerous drug companies in the production of many of the FDA-approved antiviral drugs currently on the market — and screening of compounds that allowed for numerous other drug breakthroughs, including several against previously drug resistant strains of tuberculosis and malaria. Yet, despite this record of success, researchers admit a cure for Zika will still take time.

“Even though we know a lot about flaviviruses, discovering and developing effective therapeutic agents may take several years,” Bostwick continued. “Just like any other project we’ve undertaken, we will use data as our guide and hope our efforts will yield results which can be helpful to the scientific community.”

Southern Research at 75: Targeting HIV/AIDS for 30 years

Posted on October 27, 2016

Southern Research scientists joined the front lines in the battle against HIV/AIDS in 1986, not long after the deadly viral infection emerged as a terrifying new public health threat in the United States.

Southern Research HIV/AIDS
HIV infection has been blamed for 35 million deaths across the globe.

Three decades later, the Birmingham non-profit organization is deeply involved in a broad-based initiative to find a cure for HIV infection, which the World Health Organization has blamed for 35 million deaths globally.

Scientists at Southern Research’s research center in Frederick, Maryland, are working to develop and standardize testing assays that will help researchers detect the hidden remnants of HIV in patients successfully treated with antiretroviral medications.

These hiding spots are called “latent reservoirs,” and they allow the virus to lurk unseen for years even though blood tests no longer show traces of HIV. Because the virus is not eradicated from these cellular havens, it can spring back into action when drugs are stopped intentionally or unintentionally, triggering a full-blown infection.

“In the U.S. and other developed countries, because of the availability of highly effective antiviral therapies, the virus is completely suppressed, and HIV-infected people are leading essentially normal lives. However, they still harbor the virus,” said Mike Murray, Ph.D., director of government business development for Southern Research’s Drug Development division in Frederick.

“The next step in the fight against AIDS is the cure,” he added. “The question is how do you go in and get rid of the virus completely?”

 SR 75th_Logo_Horz_RGBTo support researchers searching for that cure, Southern Research is working to expand access to what’s called the Quantitative Viral Outgrowth Assay (QVOA). Though expensive and labor intensive, the QVOA is considered the most effective testing platform for HIV/AIDS researchers trying to evaluate the latent viral reservoir.

Southern Research is also working with experts in HIV latency to develop alternative assays that are quicker, more sensitive and less costly.

TARGETING VIRAL THREATS

Southern Research’s current HIV/AIDS work builds on decades of experience in the field of viral threats.

The organization’s virus research program got started in the 1950s, and early work focused on herpesviruses, poxviruses and mosquito-borne viruses such as Yellow Fever. In the 1970s, Southern Research virologists evaluated potential drugs against the Gross murine leukemia virus, a retrovirus that causes cancer in mice.

In 1986, the organization’s Microbiology-Virology department began work on a U.S. Army contract to study antiviral activity of compounds against exotic RNA viruses.

That same year, the Army and the National Institutes of Health (NIH) asked Southern Research to evaluate compounds for the treatment of AIDS, caused by the human immunodeficiency virus, a retrovirus that has RNA as its genetic material.

Before long, Southern Research was testing 1,500 compounds a year, making it one of the first laboratories outside the NIH evaluating AIDS compounds on a major scale.

The earlier testing program on the Gross leukemia virus, along with the development of new assays for large-scale screening, prepared Southern Research to greatly expand evaluation of potential HIV/AIDS compounds. Its labs were eventually testing large numbers of synthetic chemical compounds advanced for screening against the virus, resulting in around 20,000 tests annually for a decade.

Southern Research’s anti-HIV screening program became the largest in the country, and many of the AIDS treatments now on the market were evaluated through its program.

SEEKING NOVEL TREATMENTS

Southern Research HIV/AIDS
The infectious disease labs at Southern Research began working on HIV/AIDS in 1986.

Over the years, Southern Research’s efforts against HIV/AIDS have moved forward on several fronts, based on longstanding partnerships with the National Institutes of Health and other government agencies.

In 2014, the organization received a $24 million contract from the Division of AIDS (DAIDS) at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) to provide drug discovery and development services that could lead to potential new drugs for the treatment and prevention of HIV infection.

Using high throughput screening, an automated process that rapidly assesses the activity of drug-like compounds, and preclinical studies, Southern Research scientists are seeking to identify and develop novel antiretroviral molecules against HIV.

Their focus is on therapeutics for novel viral targets not inhibited by current therapies and topical microbicides, which could neutralize the virus prior to infection.

The latent reservoir work now being done for DAIDS-NIAID puts Southern Research back on the front lines in the effort to prevent, treat, and find a cure for HIV infection, which produces around 40,000 new cases in the U.S. each year.

 “We are excited to be contributing to the HIV Cure Initiative,” said Murray, who previously headed infectious disease research for Southern Research in Frederick.

 

This is Part Eight of a series looking at the history of Southern Research.

Southern Research project aims to prevent future polio outbreaks

Posted on October 24, 2016
The polio virus is close to eradication but fears persist it could return in future outbreaks.
The polio virus is close to eradication but fears persist it could return in future outbreaks.

Poliomyelitis is a crippling and potentially fatal disease caused by a virus. As recently as 60 years ago, there were few diseases more frightening to parents of young children than polio. Today, polio cannot be cured. It is extremely rare, however, because it is safely and effectively prevented by vaccination.

With the poliovirus edging closer to eradication across the globe, Southern Research’s infectious disease labs are playing a critical role in the search for a drug that could aid the ongoing worldwide polio eradication initiative and help halt the spread of the crippling disease in a future outbreak or bio-attack.

Under a contract with the National Institute of Allergy and Infectious Diseases (NIAID), Southern Research scientists in Frederick, Maryland, are screening compounds that could prove useful against polio, as well as a related virus, coxsackie. Coxsackie virus infection is a leading cause of both acute and chronic myocarditis for which there is currently no effective treatment or vaccine.

The ultimate goal of the work is to identify a broad spectrum anti-viral agent that could be developed as a therapy to treat the highly contagious poliovirus and address the unmet medical need for an effective antiviral against coxsackie virus disease.

“Developing an anti-viral drug against polio is part of the strategy to mitigate risk associated with post-eradication exposure events, be they accidental or an intentional exposure resulting from a bioterrorist attack,” said Mike Murray, Ph.D., director of government business development for Southern Research’s Drug Development division.

“Once poliovirus is declared eradicated, the population may become more vulnerable to an outbreak because of potential changes in vaccine requirements and the rising number of parents refusing to vaccinate their children because they don’t see the need for it,” Murray added.

Moreover, Global Polio Eradication Initiative (GPEI) activities for 2013-2019 require approximately $7 billion to complete. “In this context, the reason to develop an antiviral is very simple – protect the multibillion-dollar investment made to eradicate polio,” said Murray, who previously headed infectious disease research for Southern Research in Frederick.

SEEKING A THERAPY

Southern Research’s Frederick labs have been involved in this effort with NIAID support since 2012. Murray said he’s optimistic that drug development efforts will produce a therapy against polio, though he notes bringing a drug to market is a costly process that typically takes years. Regardless, having an anti-viral drug effective against polio would be valuable, he added.

“Many people think polio is not a problem – it’s gone,” Murray said. “It’s not.”

Polio reemerged in Syria in 2013, and there were outbreaks in Somalia that year as well. Poliovirus is still circulating in Afghanistan and Pakistan, with 19 cases reported so far in 2016.

“We are involved in the strategic end game now, helping to solve one of the world’s most difficult problems, so that’s exciting. This contract is part of that,” Murray said.

REDUCING THE TOLL

Polio, or poliomyelitis, affects the central nervous system, sometimes producing paralysis. Between the late 1940s and early 1950s, polio crippled around 35,000 people each year in the United States alone, many of them children. The viral infection earned a fearsome reputation during this period.

Since then, vaccines have dramatically reduced polio’s human toll. The World Health Organization says polio cases across the globe have decreased by more than 99 percent since 1988, from more than 350,000 cases to 359 reported cases in 2014.

There are still two countries, Afghanistan and Pakistan, with endemic circulation of wild type poliovirus, and, recently, two children have been paralyzed by the disease in Nigeria after seeing no cases there for two years, said Eun Chung Park, Ph.D., NIH program officer and contract officer’s representative for the contract.

Since 2014, there have been isolated outbreaks associated with war-torn areas of the world, where vaccination is difficult or impossible, and the virus might travel with fleeing refugees.

The Bill & Melinda Gates Foundation, which has named polio eradication one of its key objectives, says the fight to end polio continues, often under some of the world’s most difficult and dangerous circumstances. It has vowed not to give up until every last child is protected.

INEVITABLE ERADICATION

Murray said polio’s eradication is inevitable, but it will not be easy. Poliovirus will become the third virus to be wiped out after a global campaign. The others are the smallpox virus, an ancient pathogen responsible for the deaths of hundreds of millions of people, and rinderpest, also known as the “cattle plague.”

As with the victory over small pox, however, there are fears that polio could make an unexpected comeback. To mitigate the risk associated with the reemergence of poliovirus, scientific research, vigilant surveillance, vaccine manufacture and new product development will continue.

The government is looking for drugs that will aid in the final eradication process and at the same time preparing for accidental exposure or nefarious use as a weapon. That’s where Southern Research contributes, Murray said.

“Poliomyelitis is still a risk. You could imagine a situation similar to measles where people become complacent or worse, refuse to vaccinate their children,” Murray said. “Then all of the sudden, there’s an outbreak. We saw this in the Disneyland measles outbreak last year. The outbreak spread to Disneyland and then to seven states and two other countries due to the virus being carried by travelers to and from the theme park.”

TARGETING COXSACKIE

Coxsackie, the other target in Southern Research’s NIAID contract, is a leading cause of both acute and chronic myocarditis, an inflammation of the middle layer of the heart wall. Coxsackievirus can also cause pancreatitis, an inflammation of the pancreas.

Today, there is neither a vaccine nor a therapeutic treatment for this viral infection.

Like polio, coxsackie is an enterovirus, a group of single-stranded RNA viruses associated with a wide range of human diseases. Taken together, the screening performed by Southern Research’s infectious disease labs provides a means to evaluate broad-spectrum therapeutics against enteroviruses.

NOTE: This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN2722010000221.

NIH director thanks Southern Research for ‘treatments, cures and real hope’

Posted on October 14, 2016

In a message to mark Southern Research’s 75th anniversary, Dr. Francis S. Collins, director of the National Institutes of Health, praised the organization’s scientists for making significant advances against cancer and other diseases.

“Since 1941, Southern Research has made advances that have helped people all across this country – in fact, all around the globe,” Collins said in a video shared with the Birmingham-based non-profit.

In particular, the leader of NIH, the nation’s chief medical research agency, noted the achievements of Southern Research’s long-standing cancer research program. The organization’s scientists played key roles in developing effective chemotherapy methods and in the discovery and development of numerous FDA-approved oncology treatments.

“Of the 200 or so drugs currently used to treat cancer, seven were discovered at Southern Research,” Collins said. “In fact, two of them – fludarabine and clofarabine – are even on the World Health Organization’s list of essential medicines.”

In addition, Southern Research has provided vital research tools and models that allowed other scientists to advance the development of cancer therapeutics, he said.

TARGETING DISEASES

While efforts to discover new oncology drugs continues at Southern Research, Collins noted that its scientists are also working on potential therapeutics for Alzheimer’s, Parkinson’s, diabetes, Lou Gehrig’s disease, and tuberculosis, among others.

At the same time, Southern Research is helping researchers around the world test new disease-fighting strategies. “The area of HIV/AIDS research has been a real standout,” he said.

Collins singled out Southern Research’s work in the field of reproductive toxicology, which seeks to prevent birth defects, and on the Zika virus, which has suddenly emerged as a serious threat to public health around the world.

Collins also responded to a letter from Southern Research CEO and President Art Tipton, Ph.D., who thanked the NIH for providing the Birmingham non-profit with more than $500 million in funding over the past three decades.

“Mr. Tipton, I want to let you, along with all of Southern Research and its supporters, know that you are indeed welcome,” Collins said. “And on behalf of the NIH and the American taxpayer, I want to thank you, Southern Research, for a tremendous return on this investment – a return measured in treatments, cures and real hope for a better future for people all around the world.

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