Current Research Activities
Severe but rare adverse drug reactions are sometimes not predicted by preclinical models and are discovered in late clinical trials or in the marketplace. A common misperception is that this deficiency in preclinical safety testing can be overcome by "humanizing" preclinical models (e.g. cultured human hepatocytes or transgenic mice), but this strategy ignores that fact that only a small fraction of the human population is susceptible to these rare toxicities. An underlying principle of The Hamner-University of North Carolina Institute for Drug Safety Sciences is that improved preclinical models will only result from understanding mechanisms, and that the best place to begin this discovery process is the study of patients who experience these adverse events. Initial research efforts focus on drug-induced liver and kidney injuries and will create a template to follow for the study of other major organ toxicities.
Podcast: Dr. Paul Watkins - IDSS Research Platforms
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The DILI-sim Initiative: A Multi-Stakeholder Partnership Aimed at Predicting Drug-Induced Liver Injury
The DILI-sim Initiative is a computational modeling effort which brings together The Hamner’s world-class expertise in toxicology, systems biology and modeling and pre-competitive knowledge and data from industry partners and the Food and Drug Administration. The goals of DILI-sim are to build a fully integrated, quantitative tool that will predict the likelihood of adverse liver events from new molecular entities across multiple species including man. DILI-sim will harmonize approaches to liver safety assessment and risk management at every stage in the life cycle of a drug.
Modeling Diversity in the Human Population
IDSS scientists utilize a panel of inbred mouse strains that comprise a genetic diversity similar to that found in the human population. Dense single nucleotide polymorphism (SNP) maps have been generated for each strain so that variation in toxicity phenotype across the strains can be readily mapped to specific genetic loci. Moreover, because the strains are completely inbred (homozygous at every genetic locus), studies that identify mechanisms underlying susceptibility can be replicated on a constant genetic background. IDSS scientists have utilized this approach to identify genetic determinants of susceptibility to acetaminophen hepatoxicity in man (Harrill et al. 2009).
An exciting opportunity being pursued by the Institute involves application of the strategy outlined above to the Collaborative Cross. The Collaborative Cross is an ongoing $50 milllion project housed at the University of North Carolina-Chapel Hill that will consist of up to 1,000 inbred strains of mice derived from 8 carefully selected founder strains. The Collaborative Cross will comprise a genetic diversity that significantly exceeds that found in the human population. This will allow much finer mapping of susceptibility loci than is currently possible. Moreover, because the complete DNA sequence is known for each of the founder strains, the complete DNA sequence of all of the derivative recombinant inbred strains can be inferred from SNP data. The Collaborative Cross is an unprecedented systems biology resource currently available only within the UNC system and at the IDSS. The Hamner Institute for Drug Safety Sciences has been awarded a large NIH grant with Dr. David Threadgill, Chair of Genetics at North Carolina State University, to investigate the ability of the Collaborative Cross to provide mechanistic insight into idiosyncratic hepatotoxicity.
Humanized in vivo Models (hepatic and immune systems)
It has become clear that some forms of severe adverse drug events, including drug induced liver injury, involve both innate and adaptive immunological responses. It is therefore likely that the failure of animal models to predict human adverse drug events results from species differences in the immune system in addition to species differences in the target organ. UNC professor and adjunct member of the Institute, Dr. Lishan Su, has developed a mouse model that has both a completely functional human immune system and liver repopulated with up to 50% human hepatocytes. This model, which is the only one of its kind, is being used to study the interplay between the human liver and the human immune system during drug-induced liver injury. For example, this model allows incorporation of specific human immune systems (HLA haplotypes) that have been associated with susceptibility to specific drug toxicities. IDSS scientists and Dr. Su are currently collaborating to investigate models containing human hepatocytes and immune system with the HLA haplotype (B5701) recently shown to confer an 80-fold increased risk of DILI after treatment with the antibiotic flucloxacillin.
It should be noted that in addition to traditional methods of detecting organ injury, the IDSS has in-house ability to assess target organ responses at the level of the transcriptome using both microarray and next generation sequencing, and to assess changes in metabolome using our dedicated NMR-based metabolomics core.
Organotypic Cell Culture Models
A pioneer in the culture of human hepatocytes, Ed LeCluyse, Ph.D., has joined the team at the Hamner Institutes to mount a major program to develop liver culture systems that will more faithfully mimic in vivo responses to drugs. The IDSS also has ongoing collaborations with companies developing improved culture models, including studying whether 3-D complex liver cultures prepared from panels of inbred strains will reproduce the across strain differences in susceptibility to hepatotoxins observed in vivo.
High Content Screening
One problem with current cell toxicity testing is that viability is typically the only parameter measured and more subtle perturbations in cell physiology go undetected. High Content Screening (HCS) utilizes high throughput confocal microscopy and a variety of florescent probes to detail subtle changes in cell physiology to detect potential mechanisms of toxicity. This technology can detect the hepatotoxic potential of compounds that would test negative in routine cell culture assays. Moreover, this approach provides mechanistic insight by identifying perturbed cellular organelles and physiological processes. These observations can be linked to specific pathways through parallel analysis of the transcriptome and metabolome. Joe Trask, a pioneer in HCS has joined the Hamner Institutes and oversees all HCS work at the IDSS.
There are no tests a physician can use to confidently make the diagnosis of drug-induced liver injury (DILI) or, once the diagnosis is suspected, identify the specific culprit drug in patients receiving polypharmacy. There is also a critical need for improved biomarkers capable of identifying a drug’s potential to cause serious liver injury early in clinical development. The IDSS is partnering with scientists around the world in major biomarker discovery efforts, including providing analytical expertise to industry sponsored clinical trials. One research effort unique to the Institute is the detection and characterization of liver derived mRNA present in circulating plasma.
It has been established in animal models that there are changes in the liver transcriptome during drug induced liver injury (DILI) that can be used to define characteristic “signatures” for the responsible toxicants. It seems likely that liver transcript signatures also exist for DILI in humans, but liver biopsy is generally avoided in clinical practice. Pfizer scientists noted that liver specific mRNAs such as albumin mRNA could be detected in cell free plasma during liver injury. IDSS investigator Dr. Rusty Thomas and his research team have extensively characterized this phenomenon and demonstrated that the mRNAs are encapsulated in membranes (microvesicles) that prevent their degradation. Furthermore, using gene arrays, his group has demonstrated in in vivo models that liver-derived transcriptional “signatures” exist in venous blood during liver injury and may yield clinically useful tests to aid physicians in diagnosis and management of DILI. Human clinical studies are now underway under the direction of Dr. Paul Watkins. Pfizer transferred the original patent to the Hamner Institutes and a subsequent patent for human application is pending.
The Science Advisory Board
The Science Advisory Board, consisting of executives from leading biopharmaceutical companies, academic scientists, and FDA, shapes the strategic scientific direction of the Institute for Drug Safety Sciences and will monitor its research progress.
IDSS Science Advisory Board Members
Robert M. Califf, M.D.
Vice Chancellor for Clinical Research
Director, Duke Translational Medicine Institute
Professor of Medicine, Division of Cardiology, DUMC
Garret A. Fitzgerald, M.D.
Director, Institute for Translational Medicine and Therapeutics,
University of Pennsylvania, Perelman School of Medicine
Peter Honig, M.D., M.P.H.
Head, Global Regulatory Affairs, AstraZeneca
Board of Directors, Orexigen Therapeutics
Advisory Board Member, Excellentia Global Partners.
Professor Kevin Park
Director, MRC Centre for Drug Safety Sciences and Head of School of Biomedical Sciences, University of Liverpool, UK
Cam Patterson, M.D.
Craige Distinguished Professor of Cardiovascular Medicine
Director, Carolina Cardiovascular Biology Center
Chief, Division of Cardiology, UNC-Chapel Hill
Carl Peck, M.D.
Adjunct Professor, University of California San Francisco, Center for Drug Development Science
Founder and Chairman, NDA Partners LLC
Alistair J.J. Wood, M.D.
Partner and Managing Director, Symphony Capital LLC
Janet Woodcock, M.D.
Director, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA)