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February 2016 - Issue 5
Welcome to Battelle’s Life Sciences Research CRO+ Today Newsletter. The Battelle Life Sciences Research team provides fast, accurate answers for discovery, safety and efficacy with our integrated scientific and technological capabilities, world-class facilities and ability to meet technical, development and regulatory needs. Battelle Life Sciences CRO+ Today will keep you up-to-date on cutting-edge life sciences research.
Research institutions around the world are scrambling to react to the latest outbreak of Zika virus. Scientists at Battelle may soon join the fight with support for development of diagnostic assays, animal models and vaccines.
While Zika has been known for decades, it was not considered a significant health threat until it was implicated as a possible cause of microcephaly, a serious birth defect. Now, it has been declared a public health emergency by the World Health Organization (WHO), and the research community is rushing to find answers to critical questions such as: how is this strain of Zika different from previous strains? What is the connection to microcephaly, and why are we suddenly seeing it now? How do we accurately identify people—especially pregnant women—who have been exposed? And what is the best way to control the spread of the disease?
The Battelle Life Sciences Research team wants to answer some of these basic questions and support development of new diagnostics, vaccines and therapies. Researchers at Battelle are planning to compare the virulence of the traditional strain of ZIKV to the more contemporary strains (French Polynesian and Brazilian) to see if the South American strain is more virulent compared to historical isolates. Understanding how the virus has changed over time could help us understand whether, how and why the newer strains may cause developmental problems that were not seen in the past with the disease.
Battelle also hopes to work on new in vitro assays to support vaccine and therapy development as well as diagnostic platforms to help with control and prevention efforts. Developing and validating diagnostic assays is a critical first step in finding an effective vaccine for Zika. Assays are required to assess immune response in previously infected patients and vaccinated subjects both in humans and in animal models. In addition, rapid field diagnostic platforms are urgently needed to help local healthcare organizations monitor the spread of disease and identify pregnant mothers who may be at risk.
Battelle Life Sciences Research has a long history of work with assay development and vaccine trail support for virulent diseases, including analysis of clinical samples collected from patients vaccinated against B. anthracis and Ebola virus. Battelle recently conducted efficacy studies for vaccines and therapies for West Nile virus, another mosquito-borne virus in the same family as Zika. Battelle also has experience developing and validating novel diagnostic devices for use by field personnel.
Additional research is needed to better understand the developmental and reproductive aspects of Zika infection. The link to microcephaly has not yet been definitively proven, and no mechanism has been identified by which the disease may cause birth defects. Rapid, reliable assays will be an important tool for studying the relationship between Zika infection and developmental and reproductive effects observed in human populations.
Currently, the lack of validated animal models presents a significant barrier to the research community. These models are needed for both basic research and for the development and validation of vaccines and therapies. While studies of infected human populations may be able to show evidence of a connection to microcephaly, researchers will need models to better analyze disease mechanisms and reproductive effects. There are many unanswered questions about how Zika affects the developing fetus: Is the fetus exposed to the virus when the mother is exposed? Is Zika able to cross the placenta? Are there critical time periods in development when exposure is most dangerous? What is the mechanism by which the virus impacts fetal development? Models are also needed to conduct required pre-clinical safety and efficacy studies. Battelle has extensive experience in developing novel models for infectious diseases, as well as developmental and reproductive toxicology (DART) capabilities.
Battelle’s response to Zika is still evolving as research needs and priorities are identified. Over the next several months, researchers at Battelle will be engaged in Zika research along multiple fronts.
Battelle offers a complete package of cardiovascular and pulmonary toxicology services for safety pharmacology, drug development and environmental toxicology.
For the most part, the current approaches to toxicity testing and safety assessment rely on a complex array of traditional studies that evaluate observable outcomes in whole animals, such as clinical signs or pathological changes that are indicative of a disease state. As noted by MacDonald and Robertson, “The approaches that have been taken to assess human risk of adverse effects from chemical exposure have changed very little over the last several decades.” For example, “The global regulatory requirements for registration of new human pharmaceutical chemicals—the data requirements have changed very little since their establishment three and sometimes four decades ago despite the dramatic advances in the sciences that are used for this activity.” Margaret Hamburg, FDA Commissioner, echoes these themes, “Most of the toxicology tools used for regulatory assessment rely on high-dose animal studies and default extrapolation procedures, and have remained relatively unchanged for decades, despite the scientific revolutions of the past half-century.” Indeed, when the FDA released its strategic plan in August 2011, the need to modernize toxicology to enhance product safety was the first of eight science priority areas identified.
Battelle recognized that significant improvements to the current “menu-driven” approach to nonclinical toxicology assessments are long overdue. Three steps were taken to achieve a new paradigm.
Step one was to move towards systems toxicology, a natural offshoot of systems biology—a holistic approach to focusing on complex interactions in biological systems. Systems toxicology is the study of perturbations of biological systems by chemicals and stressors using a holistic approach to describe the functioning organism.
Battelle then decided to build on existing strengths and capabilities. Panomics was used to monitor changes in molecular expression, imaging and other new endpoints to further characterize the perturbations, pharmacodynamics-pharmacokinetic modeling to characterize the dosimetry, and bioinformatics to iteratively integrate response data. Providing in vivo safety services to anchor systems toxicology findings with conventional toxicological parameters is consistent with the perspective offered by MacDonald and Robertson. “We feel that it is imperative that data from the newest technologies not be applied to the process of human risk assessment until the means to assess the relevance of the data that are derived from these assays are fully developed.
For step three, Battelle engaged the external strengths and capabilities of scientists and engineers from four U.S. Department of Energy national laboratories (NLs). Specifically, cooperative research and development agreements (CRADAs) were established with Brookhaven NL, Lawrence Livermore NL, Oak Ridge NL and Pacific Northwest NL to create the Battelle Center for Fundamental and Applied Systems Toxicology (B-FAST).
Read the entire paper on Drug Discovery & Development at dddmag.com.
The risks associated with tobacco products vary significantly with the type of product used and how it is consumed. A recent two-year study of the toxicity and carcinogenicity of smokeless tobacco products completed at Battelle is helping the industry understand the risks associated with oral exposure to ever-evolving tobacco formulations. The results were published in the October edition of Experimental and Toxicologic Pathology.
The comprehensive two-year oral chronic toxicity/carcinogenicity study, conducted in collaboration with researchers from the R.J. Reynolds Bowman Gray Technical Center, assessed the effects of smokeless tobacco on rodents. The test groups consisted of a tobacco blend used in snus and an aqueous tobacco extract of the same blend. Subjects were exposed to dosages of tobacco chosen to simulate potential exposure for humans ingesting smokeless tobacco or an aqueous extract of smokeless tobacco (the latter intended to simulate a snus extract, to enable bridging these data to snus epidemiology data).
Over the course of the two-year study, clear treatment-related, dose-responsive effects were observed including: (1) increases in plasma nicotine and cotinine (indicating that animals were appropriately exposed to levels relevant to human exposure) and (2) decreases in body weights. In addition, two tumor types displayed statistically significant increases in the experimental groups vs. controls: (1) uterine carcinoma in females and (2) epididymal mesothelioma in males. Three tumor types displayed statistically significantly decreased incidence trends: (1) mammary gland adenomas in females, (2) skin basal cell carcinomas in females, and (3) thyroid follicular cell adenomas in males. These increases (and decreases) in tumor trends were interpreted as not being treatment-related because: (1) there were no preneoplastic or related nonneoplastic histopathological findings in the treated rats at the 1-year or 2-year time points to suggest that any of these neoplastic findings were treatment-related, and (2) the tumor morphologies and incidences were generally within the expected range of historical controls for Wistar Han rats. Findings from this study indicate that chronic exposure of male and female Wistar Han rats to either a tobacco blend used in snus or a tobacco extract of that blend does not lead to increased toxicity or carcinogenicity, based on the specified outcomes measured.
Access the complete study here: Toxicological evaluation of smokeless tobacco: 2-year chronic toxicity and carcinogenicity feeding study in Wistar Han rats.
Dr. Daniel Sanford is an expert in working with deadly diseases. Over his career, he’s led safety and efficacy studies for medical countermeasures against anthrax, melioidosis, botulism, bubonic plague and many other pathogens and biological warfare agents.
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