Young macaques form an important part of our work at the NPRCs, helping us discover new ways of treating deadly diseases like tuberculosis, HIV/AIDS, Zika and more. Two researchers at Southwest NPRC at Texas Biomed recently went the extra mile to ensure these baby monkeys had a place to call their own.
HIV-1, the virus that causes AIDS, remains a potent global threat, especially in sub-Saharan Africa and other low-income areas. And while new treatments over the past 40 years have greatly improved the prognosis for those infected, prevention of HIV-1 infection by vaccines or immunoglobulins is not yet established.
That may change with a finding at the Southwest National Primate Research Center (SNPRC) in San Antonio, Texas. A team led by Dr. Ruth Ruprecht has shown for the first time that an antibody called Immunoglobulin M (IgM) can be effective in preventing infection in the mucosa after exposure to the virus. This is significant because an estimated 90% of new HIV-1 cases are caused through exposure in the mucosal cavities such as the lining of the sexual organs or rectum.
Rhesus monkeys at the SNPRC on the campus of the Texas Biomedical Research Institute were treated with a man-made version of IgM. Thirty minutes later, the same animals were exposed to simian-human immunodeficiency virus, a hybrid virus containing elements of the monkey and human immunodeficiency virus. Four of the six animals treated this way were fully protected against the virus.
“IgM can grab multiple particles like HIV-1 and SHIV very quickly and does not let go,” said Dr. Ruprecht. “Our study reveals for the first time the protective potential of IgM. It basically opens up a new area of research – IgM can do more than it has been given credit for.”
IgM, which had been thought by most scientists to have too short-lived a protective effect, may now lead the way to an effective barrier against HIV-1 infection.
The 2015-16 Zika outbreak in Brazil caused many babies to be born with severe brain abnormalities. It also prompted researchers at the Southwest National Primate Research Center into action. With a colony of 300 marmosets, they worked from findings which showed that Zika antibodies were present in wild marmosets, meaning they had become infected with the mosquito-borne illness. Specifically, male marmosets have been shown to mimic human disease when infected, leading researchers to ask whether pregnant female marmosets would show similar effects of infection. Marmosets have also shown symptoms similar to humans when infected with Lassa virus, Ebola, dengue and West Nile.
“There is strong interest in the scientific community in developing animal models to understand Zika virus with the goal of developing vaccines and therapies,” said lead author Dr. Suzette Tardif, a Scientist at Texas Biomedical Research Institute and Associate Director of Research at the Southwest National Primate Research Center. “We believe marmosets may be an especially relevant model for effects on infection in pregnancy.”
“We have a theory that the placenta may be a reservoir for the Zika virus, which would explain why there’s so much of it because we find a huge number of infected cells there,” said Dr. Jean Patterson, a researcher at Texas Biomedical Research Institute. She has proposed further studies on the impact of west Nile and other viruses in pregnant marmosets in an effort to pinpoint the link between these emerging diseases and fetal developmental problems in both marmosets and humans.
Researchers exposed pregnant marmosets to the Zika virus during the first half of pregnancy, which caused those pregnancies to end about two weeks after infection. The fetuses also showed evidence of brain abnormalities. For this reason, marmosets may be the “canary in a coalmine” for studying the effects of Zika on human pregnancy and fetal development.
In August 2018, Texas Biomedical Research Institute President and CEO Larry Schlesinger, MD named Deepak Kaushal, PhD, the new Director of the Southwest National Primate Research Center (SNPRC).
Dr. Kaushal joined SNPRC in January 2019, succeeding the retiring Robert Lanford, PhD As Director of SNPRC, Dr. Kaushal will be responsible for leading a national scientific resource funded by a $40 million National Institutes of Health grant and a team of nearly 150 scientists, veterinarians and animal care professionals.
Dr. Kaushal joins SNPRC after his tenure as Director of the Center for Tuberculosis Research within the Tulane National Primate Research Center (TNPRC) in Covington, La., and Professor in the Department of Microbiology and Immunology at Tulane University School of Medicine in New Orleans.
“We are excited Dr. Kaushal will be joining the Texas Biomed and SNPRC team,” Dr. Schlesinger said. “He is a world-renowned researcher whose focus in tuberculosis and HIV, specifically using nonhuman primates in TB research, is a natural fit with the Institute’s long-term vision of becoming the world leader in infectious disease research.”
Dr. Kaushal brings more than 25 years of experience working to eradicate tuberculosis, which kills more than two million people worldwide each year. Using the macaque nonhuman primate model, Dr. Kaushal’s lab tests new vaccine candidates and new drugs against the disease. A major focus of his research is to study the synergy between TB and HIV-AIDS.
“The opportunity to work in San Antonio is tremendous,” Dr. Kaushal said. “The community has a strong health science center and medical school, a network of higher education that fuels the engine of a research enterprise, strong non-profit organizations such as the Southwest Research Institute and is a vibrant, multicultural city. This is a place where technology, industry and supported research in infectious diseases can grow.”
A Bill and Melinda Gates Foundation supported researcher, Dr. Kaushal brings a portfolio of about $25 million in grant funding to SNPRC and Texas Biomed. He has authored more than 94 journal publications that have been published, are in press, in review or in revision and has presented at more than 66 scientific conferences worldwide.
He holds a PhD in biochemistry and microbiology from the University of Delhi in India and is a member of the Infectious Diseases Society of America, the American Society for Biochemistry and Molecular Biology, the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery (CTVD), the Bill and Melinda Gates Foundation working group on Nonhuman Primate Models and the AIDS Clinical Trials Group (ACTG).
Can a promising cancer drug also treat tuberculosis (TB), the world’s single deadliest infectious disease? Researchers at the Texas Biomedical Research Institute, host institution for the Southwest National Primate Research Center, think so.
The team discovered a mechanism for regulating cell death – called apoptosis – that could help control the bacterial infection that causes TB. Dr. Eusondia Arnett and her colleagues tested this concept by infecting human immune cells called macrophages with the TB bacterium, then treating those infected cells with the potential cancer treatment. The result was an 80% reduction in the growth of the TB bacterium.
“Induction of apoptosis and subsequent reduced growth of the TB bacterium should ultimately result in less inflammation and damage to the lungs, and increased control of TB,” said Dr. Arnett.
One-fourth of the world’s population is infected with TB, according to the Centers for Disease Control and Prevention, including 9,000 new cases in the United States in 2017. Up to 13 million people in America carry the latent TB infection, with 5-10% developing infectious TB in their lifetimes. (The majority of those infected were born outside the U.S. and infected prior to arriving in the country from areas of the world where TB is more common.)
TB infection also creates dense cellular structures, called granulomas, in the lungs of infected persons. Granulomas are the body’s attempt to wall off an infection it is unable to eliminate. But they also provide a niche for the bacteria to become resistant to antibiotics. Dr. Arnett’s study showed that these experimental cancer drugs also reduced TB bacteria growth in granulomas in a human model, holding promise for these drugs in humans and animals.
Dr. Larry Schlesinger, President and CEO of Texas Biomed, said this finding highlights the critical role of basic scientific research.
“When we study important host cell pathways for disease, we can find relationships we didn’t even know existed,” he explained. “We can forge new ways to use current knowledge to create novel strategies for therapy for infection to be used along with antibiotics.”
The drugs used in this study are already in Phase II of Food and Drug Administration clinical trials. The next step for testing the drugs’ effectiveness in treating TB is a mouse model, followed by nonhuman primate models and ultimately, human clinical trials.
An estimated 130-150 million people around the globe are living with chronic hepatitis C infection. Thanks to chimpanzees, there is now a one pill per day, 12-week cure that has already improved more than half a million lives.
As a scientific animal model, chimpanzees have played an integral role in advances against this group of deadly viruses. Without the use of these nonhuman primates with their close genetic relationship to people, many of the modern interventions, including a curative regimen for hepatitis C, might not be available today.
In a recent review article published in the ILAR Journal of the Institute for Laboratory Animal Research, Robert Lanford, of the Southwest National Primate Research Center and his co-authors present a wide-ranging, detailed look at how chimpanzee research has positively impacted human health specifically by helping bring about breakthroughs in the treatment of hepatitis.
The National Institutes of Health began chimpanzee breeding in the U.S. in 1960. The NIH has halted all further research using chimpanzee models, and Lanford points out that at research facilities and at Chimp Haven in Louisiana, “the animals are enjoying their retirement.”
In his summary, Lanford writes “entire generations are immune to HAV (hepatitis A) and HBV (hepatitis B) because of vaccines developed in the chimpanzee that are in widespread use globally.” With HBV chronic infection affecting more than 250 million people, he observes that “the loss of the chimpanzee model has stymied development of curative therapies for this infection.” Lanford goes on to suggest the scientific community needs to develop improved mouse models and even a new nonhuman primate model for this disease.
Over time, the article concludes, future generations will look back positively on the impact the chimpanzee animal model has had on human health. Hepatitis will be a disease of the past, much like polio and smallpox are today.
Imagine a day where we’re able to treat some of the world’s most debilitating neurological disorders, like Parkinson’s, strokes and brain injuries. While this day may seem far removed, scientists at the Southwest National Primate Research Center (SNPRC) are taking steps toward making the dream a reality.
Dr. Marcel Daadi of SNPRC is developing a more effective method for delivering neural stem cells to the brain in an effort to move forward stem cell therapies to treat neurological disorders. His research has already developed stem cells capable of becoming the type of cells Parkinson’s patients lose over time, or dopaminergic cells. An MRI-guided technique to implant these cells would move scientists one step closer to delivery of this therapy to patients.
“Stem cell-based therapy is emerging as a promising treatment for a variety of diseases and injuries. The first step in evaluating the potential of different therapeutic stem cell lines is to develop a safe and effectively reproducible delivery system,” Dr. Daadi explained.
Injection parameters have been well studied in drug delivery methods; however, they simply cannot be directly applied to stem cell-based therapy and the technology for stem cell delivery is undeveloped and limited.
Dr. Daadi and his colleagues developed an operational technique for delivering stem cells with low invasiveness and high accuracy in placement of the stem cells to the basal ganglia part of the brain. The basal ganglia controls motor skills compromised in Parkinsons disease.
The team tested the technique on baboons at SNPRC and not only showed effective targeted delivery but also revealed the cells were not released at a steady rate but instead dispersed in small bursts. This is a significant finding as it demonstrated how injected cells disperse in the host brain and stimulates new ideas on how we can prepare the cells to function at their best.
“We wouldn’t have been able to see this phenomenon using standard stereotaxic delivery,” Dr. Daadi said. “With iMRI, we can visualize in real time the cells being injected to the target area. A non-invasive MRI approach is becoming a necessity in clinical applications to enhance the safety of patients and the efficacy of the therapeutic approach. We can create the best cells, but if we can’t transplant them to the patient in a consistent and predictable way so that the patient can accept and thrive from them, then the therapy is simply ineffective.”
The West African outbreak of Ebola virus in 2014 made Ebola a household word. The outbreak made clear that infectious diseases know no borders and have global impact.
Ebola first emerged 40 years ago, spreading its deadly symptoms across South Sudan and the Democratic Republic of Congo. According to the World Health Organization, Ebola has a 50% average mortality rate. During the 2014-2016 outbreak, the disease infected over 28,000 people in West Africa and killed over 11,000. Currently, there are no FDA-approved treatments or vaccines for the Ebola virus – but the team at Texas Biomedical Research Institute and the Southwest National Primate Research Center is working to change that.
These scientists are working with the National Institutes of Health, the Biomedical Advanced Research and Development Authority (BARDA) and the Department of Defense to develop assays and evaluate vaccine and therapeutic candidates.
Most recently, a group of Texas Biomed scientists led by Dr. Ricardo Carrion and Dr. Anthony Griffiths was awarded a $6.6 million contract in November 2017 from the Biomedical Advanced Research and Development Authority (BARDA) to test a drug cocktail for efficacy against Ebola virus disease. These well-regulated, controlled studies that will begin in 2018 are a critical next step before declaring this drug cocktail safe and effective in humans.
“Texas Biomed is the only Institute of its kind in the country, with two extraordinary resources in one place – the BioSafety Level – 4 (BSL-4) facilities and nonhuman primate colonies,” said Scientist and Director of Texas Biomed’s BSL-4 laboratory Dr. Robert Davey.
In 2015, after discovering that tetrandrine works to stop the Ebola virus, Dr. Davey and his lab wondered: how can we move this herbal remedy into the clinic?
He has since teamed up with scientists at the Southwest Research Institute (SwRI) to develop a synthetic route to make safer versions of tetrandrine with better clinical properties as potential therapeutics against the virus. To support their scientific studies, the team of researchers received an NIH research and development contract worth up to $4.1 million.
From helping diagnose a disease to curing them, scientists at Texas Biomed and the Southwest National Primate Research Center continue the fight against pathogenic invaders and the search for new ways to approach global health threats.
