Virtual Continuing Education Courses
SOT is pleased to offer the Continuing Education (CE) courses originally scheduled for the 2020 SOT Annual Meeting as live webinars. This web page contains the schedule of the CE course webinar presentations. Please note that these webinars will be recorded and available for viewing at any time by course registrants.
If you registered for the CE course(s) as part of your annual meeting registration, you will have access to the live webinar and recording of the respective course.
Anyone may register to attend and view any of the CE courses.
In addition and as always, the digital CE course books remain available for download by course registrants at any time by viewing the specific course information on this web page.
2020 Virtual CE Course Availability and Schedule
If you have any questions or issues pertaining to the download of the Course Books noted below, please contact SOT Headquarters.
Course Recordings Available
SR01 SUNRISE COURSE
Cheryl Rockwell, Michigan State University; and Elena Demireva, Michigan State University.
Continuing Education Committee
Mechanisms Specialty Section; Molecular and Systems Biology Specialty Section
CRISPR-Cas-based technologies have revolutionized science by significantly decreasing the time, money, expertise, and labor required to implement gene editing. Thus, this approach is becoming routine in many laboratories as a facile method to alter the genome. And yet, CRISPR-based methodologies continue to evolve. Recent publications demonstrate that CRISPR gene editing can be expanded in new directions to widen the utility and potential applications of this technology. The first presentation in this course will provide an overview of the latest developments in CRISPR-Cas-based techniques, with a focus on new Cas9 variants with new and expanded capabilities. The first presentation also will cover the new field of RNA targeting and the use of pooled CRISPR libraries with single cell transcriptomics to characterize complex phenotypes. The second presentation will focus on the use of CRISPR-Cas9-based screens from a toxicologist’s perspective. Specifically, this presentation will discuss how such screens can be used to gain a detailed, mechanistic understanding of a toxicant’s effect as well as the role of specific genes. Overall, this course is designed to provide an overview of the most recent advances in CRISPR-based technologies as well to provide some insight into future uses.
Latest Advances in CRISPR-Cas Technologies. Elena Demireva, Michigan State University, East Lansing, MI.
Use of CRISPR/Cas9-Based Genome-Wide Screens in Toxicology from a User’s Perspective. Christopher Vulpe, University of Florida, Gainesville, FL.
AM03 MORNING COURSE
Kathleen Krenzer, Iuvo BioScience; and Hiromi Hosako, Alcon.
Ocular Toxicology Specialty Section
Biotechnology Specialty Section; Comparative Toxicology, Pathology, and Veterinary Specialty Section
No longer are eye drops the only way to treat the eye; the emergence of novel therapeutic and development approaches for ocular indications has impacted how we design toxicology assessments, select species, and perform toxicity evaluations. Additionally, the structural complexity of the eye as well as the unique aspects of ocular dose-administration routes require continued refinements of ocular evaluation techniques and assessment strategies. The goal of this course is to provide toxicologists with a broad overview of highly specialized ocular anatomy, current ophthalmic diagnostic techniques, evolving histopathological assessment strategies, and thought-provoking ocular drug development strategies, including case studies. The first speaker will open the session with an detailed overview of ocular anatomy complexity, focusing on unique features of the eye and critical anatomical and physiological features that may influence or impede a drug’s efficacy and safety in human patients. The speaker also will discuss novel routes of drug administration in ocular drug development. The second presentation will tune in to gold-standard, in-life ophthalmic diagnostic techniques with selected case examples showing how modern ocular diagnostic equipment can be used to prove multifactorial questions. This presentation also will touch upon recent efforts at harmonization of ocular finding nomenclature and clinical record-keeping lexicon in preparation for SEND (Standard for Exchange of Nonclinical Data) requirements dictating reporting of ocular toxicology studies. The third talk will focus on evolving strategies for histopathological assessment of ocular tissues, which will include key points to consider when processing the eye to ensure a thorough examination of key structures of the globe as well as the effect of factors such as the route of administration and the formulation or character of the therapeutic candidate on effective examination of the eye. The last presentation will highlight unique nonclinical safety challenges and considerations during ocular drug development using case studies to push our assumptions of what is the best way to evaluate the safety of ophthalmic therapeutics.
Do Animals See 20/20? The Spectrum of Ocular Anatomy and Physiology in Animals. Seth Eaton, University of Wisconsin–Madison, Madison, WI.
Getting the 20/20 Read: Clinical Evaluation Techniques for Ophthalmic Toxicology. Joshua T. Bartoe, Northern Biomedical Research Inc., Norton Shores, MI.
20/20 under the Scope: Evolving Strategies for Histopathological Assessment of Ocular Tissues. Helen Booler, Genentech Inc., South San Francisco, CA.
Using 20/20 Hindsight to Set the Course for Considerations in the Preclinical Development of Ocular Therapeutics in the Future. Brenda Smith, Allergan, Irvine, CA.
AM04 MORNING COURSE
Agnes Karmaus, Integrated Laboratory Systems, Inc.; and Nicole Kleinstreuer, NIEHS/NICEATM.
In Vitro and Alternative Methods Specialty Section
Mechanisms Specialty Section; Regulatory and Safety Evaluation Specialty Section
Computational toxicology is rapidly accelerating our ability to develop methods for predicting chemical properties and chemical-mediated effects, both in the environmental chemical space and in the area of drug development. With frequently updated tools and approaches, overwhelming feedback suggests that more training is needed to help all toxicologists understand the fundamental approaches, use available tools and databases, and interpret outputs. This CE course is designed to offer an introductory-level foundation for leveraging some widely accepted approaches and demonstrate how to use open-source tools and resources to make use of these methods. Course participants across all sectors, ranging from students to career toxicologists, should walk away with the confidence to use the resources presented for computationally characterizing and predicting chemical-elicited toxicity. In addition to gaining familiarity with basic computational toxicology concepts, participants will gain insight into what makes an approach useful for research projects versus which are ready for potential regulatory applications. The first speaker will help lay a foundation for how chemicals are “interpreted” computationally, explaining how chemical structures are leveraged for subsequent analyses (i.e., fingerprinting and its use for read-across). Building on these concepts, the second speaker will provide a thorough example of how to use the US Environmental Protection Agency (US EPA) CompTox Chemicals Dashboard, which provides data for nearly 900,000 chemicals and drugs. Attendees will learn how to assess the confidence in available data, as well as learn how to use the tools available in the dashboard for predicting chemical toxicity and download pertinent data, including mechanistic information, exposure data, animal toxicity doses, and much more. The third presentation will provide a demonstration to empower course attendees in using the Integrated Chemical Environment (ICE), an interactive tool that contains in vitro to in vivo extrapolation workflows that users can leverage to conduct analyses themselves, as well as provides curated in vivo and in vitro datasets that can be used to evaluate predicted toxicology outcomes. The fourth presentation will steer the course further into the realm of biological interpretation, describing how toxicogenomics data and literature mining underlying the Comparative Toxicogenomics Database (CTD) can be utilized to computationally characterize chemical mode of action and provide insight into toxicity mechanisms. The last speaker will introduce Sysrev, a collaborative computational systematic review tool to extract pertinent data from literature, incorporating approaches such as machine learning and metadata tagging. Overall, course attendees will gain a fundamental understanding of approaches underlying the most widely used computational toxicology methods, as well as learn to use publicly available, open-source tools that apply these methods.
Course Introduction: What Do Computational Toxicology Tools Offer? Nicole Kleinstreuer, NIEHS/NICEATM, Durham, NC.
Cheminformatics 101: Fingerprinting and Read-Across. Mark Cronin, Liverpool John Moores University, Liverpool, United Kingdom.
The US EPA CompTox Chemicals Dashboard. Antony Williams, US EPA/NCCT, Research Triangle Park, NC.
Integrated Chemical Environment (ICE). Shannon Bell, Integrated Laboratory Systems, Inc., Durham, NC.
Comparative Toxicogenomics Database (CTD). Carolyn Mattingly, North Carolina State University, Raleigh, NC.
Sysrev: Collaborative Literature Extraction. Tom Luechtefeld, Insilica, Baltimore, MD.
AM06 MORNING COURSE
Kan Shao, Indiana University; and Weihsueh A. Chiu, Texas A&M University.
Risk Assessment Specialty Section
Biological Modeling Specialty Section; Regulatory and Safety Evaluation Specialty Section
Quantifying dose-response relationships to evaluate the toxicity of environmental chemicals is a key step in human health risk assessment and has evolved substantially in recent years. In addition to fundamentally developing a dose-response curve and estimating a dose level that results in a predetermined critical effect, recent advances in toxicology and modeling strategies enable dose-response assessment to more comprehensively and quantitatively address uncertainty and human variability. The purpose of this course, to be delivered by a mixed group of experts from academia, government, and industry, is to provide participants an overview of the cutting-edge modeling strategies employed in dose-response assessment to quantify uncertainty and variability. The first presentation will introduce the benchmark dose (BMD) methodology and its utilities to quantify various sources of uncertainty in dose-response modeling with a demonstration of the Bayesian BMD modeling system. The second speaker will present an overview of the principles and recent applications of probabilistic dose-response assessment approaches developed under the WHO/IPCS guidance to address uncertainty and variability in quantitative risk assessment. The third presentation will provide an overview together with case examples of Diversity Outbred (DO) mouse population-based in vitro systems to demonstrate a data-driven probabilistic approach to derive a chemical-specific uncertainty factor for inter-individual variability. The last speaker will introduce how to predict population distributions of toxicokinetic-relevant physiological quantities that NHANES does not measure based on the measured counterparts using the HTTK-Pop R package that incorporates population variability in high-throughput toxicokinetic modeling. Throughout the course, use of and applications to in vitro and high-throughput testing systems will be highlighted, including their relevance to in vitro to in vivo extrapolation (IVIVE).
Benchmark Dose Modeling Strategies for Uncertainty Quantifications in Dose-Response Assessment. Kan Shao, Indiana University, Bloomington, IN.
Probabilistic Dose-Response Assessment to Quantitatively Address Uncertainty and Variability. Weihsueh Chiu, Texas A&M University, College Station, TX.
Modeling Dose-Response across Populations: Quantification of Inter-Individual Variability. Alison Harrill, NIEHS, Research Triangle Park, NC.
Simulation of Population Variability in High-Throughput Toxicokinetic Modeling in Support of Dose-Response Assessment. Caroline Ring, ToxStrategies Inc., Austin, TX.
AM07 MORNING COURSE
Andrew Parkinson, XPD Consulting; and Brian Ogilvie, Sekisui XenoTech LLC.
In Vitro and Alternative Methods Specialty Section
Drug Discovery Toxicology Specialty Section; Exposure Specialty Section
In the current landscape of drug development and investigation of environmental chemicals, many personnel with toxicology backgrounds find themselves overseeing not only preclinical safety assessments but also in vitro xenobiotic metabolism and interaction studies. Therefore, the goal of this course is to provide attendees with practical perspectives from experts in the field on the approaches and techniques that are available to address the important aspects of xenobiotic metabolism. The first presentation will focus on the experimental design and interpretation of data obtained from studies of in vitro inhibition of cytochrome P450 (CYP) and other xenobiotic-metabolizing enzymes. In contrast, the second presentation will focus on the experimental design and interpretation of data obtained from studies of in vitro induction of CYP and other xenobiotic-metabolizing enzymes. The third talk will broaden considerations of xenobiotic metabolism, including assessment of the toxicological burden of reactive metabolites, and the experimental design and interpretation of data obtained from studies of in vitro reaction phenotyping techniques in human liver microsomes and other test systems derived from humans or toxicologically relevant species. The fourth presentation will discuss in vitro approaches for determining the potential for xenobiotics to be substrates or inhibitors of major transporters that are of regulatory interest and interpretation of the data obtained from these studies. The final presentation will discuss the practical implications of the in vitro approaches discussed and the current regulatory thinking on their applicability to all xenobiotics to which humans are exposed. The overarching objective of this course is to provide attendees with a solid foundation in commonly used methods to enable the design, execution, and interpretation of rigorous and reproducible in vitro xenobiotic metabolism and interaction studies that will withstand regulatory scrutiny and avoid common pitfalls. This course will benefit those whose toxicological interests are expanding to include in vitro xenobiotic metabolism, as well as professionals responsible for appraising or evaluating in vitro xenobiotic metabolism, interaction studies, and other ADME data for internal decision-making, risk assessment, or submission to various regulatory agencies.
Introductory Remarks on Xenobiotic Metabolism and Course Overview. Andrew Parkinson, XPD Consulting, Shawnee, KS.
The Basics of In Vitro CYP Inhibition Studies for Regulatory Submission and Risk Assessment. Brian Ogilvie, Sekisui XenoTech LLC, Kansas City, KS.
The Basics of In Vitro CYP Induction Studies for Regulatory Submission. Diane Ramsden, Alnylam Pharmaceuticals Inc., Cambridge, MA
In Vitro Reaction Phenotyping and the Toxicological Burden of Reactive Metabolites. Jed Lampe, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO.
Xenobiotic Transporter Studies for Regulatory Submission. Caroline Lee, Arena Pharmaceuticals Inc., San Francisco, CA.
The Science of Drug Interactions Is Applicable to All Xenobiotics. Andrew Parkinson, XPD Consulting, Shawnee, KS.
PM10 AFTERNOON COURSE
Mansi Krishan, Danone North America; and Suzanne Fitzpatrick, US FDA/CFSAN.
Risk Assessment Specialty Section
Drug Discovery Toxicology Specialty Section
Recent shifts in the global regulatory landscape to consider the use of nonanimal testing methods have led to significant advances in the development of alternative test methods to replace, reduce, and refine animal use. The term new approach methodologies (NAMs) broadly describes any nonanimal technology, methodology, approach, or combination that can be used to provide information on chemical hazard and risk assessment. With new opportunities comes new challenges, such as validation of test results, understanding their applicability in different sectors and risk assessments, and global regulatory acceptance of these methods. Despite these challenges, the development, use, and acceptance of these predictive toxicology methods is on the rise. There is a wealth of knowledge and data that is being generated with NAMs; however, there are questions on when, how, and where can we use these NAMs. This CE course will provide an overview of NAMs along with case studies where they are being used or could potentially be used for regulatory risk assessment. The speakers will present on (1) chemical-biological data and analysis tools (Tox21/ToxCast) and examples where high-throughput screening (HTS) methods have been approved for use in regulatory decision-making; (2) read-across approaches and their use in regulatory risk assessment; (3) use of evidence maps and systematic reviews and case studies with a focus on application of each to regulatory risk assessment; (4) use of the adverse outcome pathway (AOP) including most well-developed examples of AOP-supported decision processes for evaluating skin sensitizing potential and a computational model to predict the likelihood of reproductive impairment based on aromatase inhibition; and (5) concepts underpinning Integrated Approaches to Testing and Assessment (IATA) and concrete examples for assessing developmental neurotoxicity (DNT) and carcinogenicity of chemicals used in a variety of sectors. Also, updates will be provided on IATA case study projects currently running at the OECD and a set of resources being developed to support IATA development, evaluation, and regulatory uptake. This course will be useful to those interested in understanding the regulatory application of NAMs.
Chemical Bioactivity Data and Useful Analysis Tools for You to Explore. Nisha Sipes, NIEHS/NTP, Durham, NC.
Building Confidence in Read-Across Conclusions with NAMs. Craig Rowlands, Underwriters Laboratories R&D, Northbrook, IL.
Systematic Reviews: Application in Regulatory Risk Assessment. Kristina Thayer, US EPA, Research Triangle Park, NC.
The Adverse Outcome Pathway (AOP) and Its Use to Support Regulatory Risk Assessment. Catherine Willett, Humane Society International, Jamaica Plain, MA.
Overview and Case Studies to Demonstrate the Use of Integrated Approaches to Testing and Assessment (IATA) in Regulatory Risk Assessment. Maurice Whelan, European Commission Joint Research Centre, Ispra, Italy.
PM12 AFTERNOON COURSE
Jessica Lynch, Janssen Research & Development; and Rafael Ponce, Shape Therapeutics.
Immunotoxicology Specialty Section
Biotechnology Specialty Section; Regulatory and Safety Evaluation Specialty Section
Cancer immunotherapy is an area that has been of great interest in the last few years as several new therapeutic approaches have shown encouraging results in the clinic and subsequent approvals. The normal immune system has a protective capacity against tumor cells (immunosurveillance), while tumors can employ mechanisms that can result in an insufficient supply of activated and/or antigen-specific T cells within the microenvironment (tumor evasion). To overcome this immune-evasive mechanism, T cells can be redirected and expanded within the tumor microenvironment. CD3 redirection, which leverages protein-based therapeutics to simultaneously bind CD3 on T cells and a tumor associated antigen (TAA) on tumor cells, and engineered T cell–based therapeutics to redirect T cells to TAAs are emerging as powerful ways to harness the immune system to combat malignancies.. The goal of this course is to provide the investigator with an overview of T cell redirection technologies and how to design a nonclinical safety strategy to understand safety liabilities. An overview of chimeric antigen receptor (CAR) T cells, T cell receptor (TCR) T cells, CD3 bispecifics, and immune mobilizing monoclonal TCRs against cancer (ImmTac) modalities will be provided. In addition, successful nonclinical safety strategies to support first-in-human clinical trials for these modalities will be shared. Overall, this course will provide a comprehensive overview of T cell redirection platforms, study design, and the challenges associated with these modalities.
An Introduction to Cancer Immunotherapy and the T Cell Redirection Course. Jessica Lynch, Janssen Research & Development, Spring House, PA.
Generation of Synthetic Tumor Immunity through the Development of T Cell Redirecting Modalities. Rodney Prell, Genentech Inc., South San Francisco, CA.
Engineered T Cells as Cancer Therapeutics: An Update on Their Design, Manufacture, and Clinical Experience. Rafael Ponce, Shape Therapeutics, Seattle, WA.
Preclinical Safety Assessment of CAR and TCR T Cell Therapies. Thomas Long, Juno Therapeutics, Seattle, WA.
Getting the Most Out of Your Nonclinical Safety Studies for Antibody-Based CD3 Redirectors to Inform Deselection or Enable First-in-Human Clinical Trials. Jacintha Shenton, Janssen Research & Development, Spring House, PA.
Regulatory Perspective on the Preclinical Development of T Cell Immunotherapies. Alyssa Galaro, US FDA/CBER, Silver Spring, MD.
PM13 AFTERNOON COURSE
Amy Clippinger, PETA International Science Consortium Ltd., United Kingdom; and Emily Reinke, Army Public Health Center.
In Vitro and Alternative Methods Specialty Section
Inhalation and Respiratory Specialty Section; Regulatory and Safety Evaluation Specialty Section
Inhalation is a major route of human exposure to airborne substances, and as such, there are regulatory and nonregulatory needs to assess the potential toxicity of inhaled substances. While the standard regulatory requirement is a rat inhalation toxicity test, anatomical and physiological differences between rodents and humans have led to substantial investment in the optimization of alternative approaches. These alternative approaches can be based on human mechanisms of toxicity, thus better protecting human health while reducing animal use. In this course, speakers from government, contract research organizations, academia, and NGOs, as well as method developers, will discuss progress and challenges associated with various approaches for inhalation toxicity testing. It will include an introductory overview, setting the stage for the remaining talks by discussing the currently used rat inhalation tests and how an alternative approach can be demonstrated to be a valid replacement. Other topics to be covered will be the use of cell culture systems, 3D reconstructed human tissue models, and human precision-cut lung slices, as well as the use of in vitro exposure devices for deposition of test chemicals. The final speaker will present a regulatory perspective on processes in place that allow for acceptance of alternative approaches for inhalation toxicity testing, highlighting a successful example. These presentations will explore the value of the air-liquid interface (ALI) for testing, advantages and limitations of different approaches, and case studies of the use of different model systems in both nonregulatory and regulatory paradigms. Overall, a course attendee should learn about the state-of-the-science of in vitro approaches for respiratory toxicity testing and gain insight into determining which method is most appropriate, depending on the test substance and purpose of the study. This course is aimed at scientists at all levels from industry, government, and academia.
Regulatory Landscape and Key Considerations for Establishing Inhalation Reference Data. David Allen, Integrated Laboratory Systems Inc., Research Triangle Park, NC.
Current Status of In Vitro Models to Evaluate Pulmonary Toxicity. Arno Gutleb, Luxembourg Institute of Science and Technology, Esch-sur-Alzette, Luxembourg.
3D In Vitro and Ex Vivo Pulmonary Test Systems Provide Human-Relevant Toxicity Data. Holger Behrsing, Institute for In Vitro Sciences Inc., Gaithersburg, MD.
Regulatory Use of Nonanimal Approaches for Assessing Inhalation Toxicity of Pesticides. Monique Perron, US EPA/OPP, Washington, DC.
PM14 AFTERNOON COURSE
Vicki Sutherland, NIEHS/NTP; and Nicole Principato, Bristol-Myers Squibb Company.
Reproductive and Developmental Toxicology Specialty Section
Comparative Toxicology, Pathology, and Veterinary Specialty Section; Regulatory and Safety Evaluation Specialty Section
The male reproductive system develops in utero—in rats during mid-gestation and in humans during the second month of pregnancy—but does not fully mature until puberty. Exposure to xenobiotics (e.g., diethylstilbestrol and phthalate exposure) during any stage, particularly during development and maturation, can adversely affect a male’s reproductive potential and play a significant role in development of a diseased state. Understanding what normally happens at these critical stages of development can lend clues to determine when an exposure has happened, what tissues are affected, and if functional capabilities will be impacted. Defining potential effects is routinely performed with guideline reproductive and developmental experiments and in academia with focused studies; however, these assessments do not always include histopathology evaluations, and if they do, the rigor needed for select tissues may not be utilized. Inclusion of histopathology, especially during select stages, may help identify a pattern of toxicities, subtle effects of an endocrine-disrupting chemical, or lesions that can lead to future reproductive issues (e.g., infertility). This additional data can expand our capabilities in characterizing potential modes of action that result in functional changes. Thus, a field that did not routinely assess tissues in more than a functional manner is now exploring the utility of pathology evaluations at stages not previously studied (e.g., juvenile assessment of cell populations in the testes) and appreciating that these tools can assist in recognizing patterns of toxicity. Therefore, a full toxicological and histopathology assessment of the male reproductive tract may provide additional information on functional effects, assist in determining which part of the system was targeted and how to mitigate concerns, and, for select issues, provide an early read on potential problems. This course will cover development and maturation of the male reproductive tract, explaining impacts on function at different time periods (in utero, juvenile, and adult) and addressing the potential value of histopathology at both the juvenile and the adult stages. Case studies will be used to highlight the toxicological significance of the effects of xenobiotics on male reproductive system toxicity. Understanding patterns of toxicity (e.g., effects in organ weight linked with findings in other tissues or pathology findings observed in a young animal correlating to outcomes in an adult) and utilizing some of the newer techniques and protocols (e.g., fetal testis explants, biomarkers) will not only provide a better understanding of what endpoints are affected but also may provide us with the tools to design better studies and correlate findings at earlier stages with long-term functional effects. To this end, four speakers, each a world-recognized expert in male anatomy, development, reproduction, and/or pathology, will discuss functional assessments of the male reproductive tract and address the utility of pathology in male reproductive and development evaluations.
An Overview of the Male Reproductive System: Applied Anatomy and Physiology from a Pathologist’s Perspective. Justin Vidal, Charles River, Matawan, MI.
Pathology in Reproductive Toxicology Assessments and the Role of Stage-Awareness for Testis Evaluation. Cynthia Willson, Integrated Laboratory Systems Inc., Research Triangle Park, NC.
Postnatal Development of the Juvenile Male Reproductive Tract in Rats: Microscopic Evaluation, Interpretation, and Time Points of Toxicologic Significance. Catherine Picut, Charles River, Durham, NC.
Prenatal Development of the Male Reproductive Tract in the Rat, Dog, and Human: Critical Developmental Windows and Later-Life Consequences of Exposure. Kim Boekelheide, Brown University, Providence, RI.
Friday, May 29
11:00 AM–2:30 PM (ET)
AM08 MORNING COURSE
Alessandro Venosa, University of Utah; and Jamie DeWitt, East Carolina University.
Immunotoxicology Specialty Section
There is compelling evidence that exposure to exogenous agents at different stages of development contributes to disease later in life (and across generations), with animal models supporting this concept in reproductive, metabolic, and neurodegenerative diseases. Two major notions link prenatal and early-life exposure to increased risk of disease later in life—namely, the Barker hypothesis and the hygiene hypothesis—while epigenetic reprogramming may extend this susceptibility across future generations. The immune system represents a unique niche of cells tightly entangled with the parenchyma in every tissue, acting as pro-homeostatic sentinels equipped to mount the appropriate response upon exogenous aggression. While the linkage between developmental immunotoxicity (DIT) and susceptibility to later-life diseases is an accepted paradigm, the mechanisms by which exogenous agents impact the developing immune system and change disease susceptibility are not well established. Clinical evidence suggests that the underlying effects of these agents may be masked until triggered by a later-life event (i.e., infectious exposure or aging itself), at which point the immune response may enact a super-responsive state, favoring disease pathogenesis. Recent evidence highlights myriad variables to take into account to accurately study DIT, including the importance of evaluating the appropriate window of vulnerability; establishing whether the toxicant exerts direct and long-lasting effects on the immunological machinery or reprograms the behavior of bystander parenchymal cells; outlining which pathway each environmental agent will be affecting; and, more recently, determining sex-based outcomes to exposure. With basic and translational researchers facing the challenge of elucidating the molecular mechanisms mediating DIT, it is pivotal that regulatory agencies and industry work in unison toward implementing safety protocols that address these factors. Therefore, this Continuing Education course proposes to (1) inform the attendees on the current advances in the design and execution of DIT studies geared at developing preclinical tools to predict risk of adult-life disease; (2) provide the most recent evidence, spanning multiple phylogenetic species (nonhuman primates, rodents, and fish), of DIT across a wide array of exogenous agents; and (3) provide insights on the impact that studying DIT could provide at the regulatory level.
Introduction to the Course and Overview of Developmental Immunotoxicity. Alessandro Venosa, University of Utah, Salt Lake City, UT.
Development of the Immune System across Phylogenetic Classes. Mark Collinge, Pfizer Inc., Groton, CT.
Design and Implementation of Studies to Detect Developmental Immunotoxicity in Young and Adult Organisms. Victor Johnson, Burleson Research Technologies Inc., Research Triangle Park, NC.
Zebrafish as a Model for Developmental Immunotoxicity. Jessica Plavicki, Brown University, Providence, RI.
Early-Life Exposure and Later-Life Disease. Jamie DeWitt, East Carolina University, Greenville, NC.
Regulatory Impacts of Developmental Immunotoxicity. Ellen Hessel, Rijksinstituut voor Volksgezondheid en Milieu (RIVM), Bilthoven, Netherlands.
12:00 Noon–1:00 PM (ET)
SR02 SUNRISE COURSE
Robert Young, MilliporeSigma; and Vincent Reynolds, Eli Lilly and Company.
Regulatory and Safety Evaluation Specialty Section
Biotechnology Specialty Section; Carcinogenesis Specialty Section
This session will provide an educational opportunity for attendees interested in learning how information from adverse outcome pathways (AOPs) can be leveraged with two recent US Food and Drug Administration (US FDA) initiatives (i.e., the Biomarker Qualification: Evidentiary Framework and the Predictive Toxicology Roadmap) to improve decision-making for toxicology and human safety issues. The biomarker framework is aimed at identifying and qualifying biomarkers that, within a defined context of use, can be used reliably for specific interpretations and applications. The predictive roadmap is a call to action highlighting the need for a comprehensive strategy to assess new methods and technologies that can improve predictive capabilities, minimize the use of animals, and guide decision-making in regulatory reviews. Because firsthand industry knowledge with these regulatory initiatives may be limited, it is important that experience and learnings available to date be broadly communicated. This session will open with a discussion of ongoing efforts to use AOPs as tools to enhance our mechanistic understanding of various toxicities and to use networks of AOPs as the basis for biomarker development. An example of the genesis and application of biomarkers will be discussed in the context of efforts to develop comprehensive predictions of liver cancer in rodents, including their use in de-risking compounds that would cause cancer through rodent-specific mechanisms. From this initial presentation, session attendees will gain an increased appreciation of the importance of exploiting opportunities for mechanistic screens incorporating biomarkers to define the AOP through which a chemical may mediate effects. The session will then ask a crucial question: After identification of a potentially useful biomarker, what are the next steps needed to ensure regulatory acceptance? To address this point, the second presentation will summarize how the Biomarker Qualification: Evidentiary Framework can be used to define the steps needed to validate the linkage of a biomarker with a specific toxicity or mechanism and provide advice—including a list of dos and don’ts—on how to move efficiently through the process needed to ensure regulatory acceptance of the biomarker for its intended purpose(s). The value of this approach when interacting with regulatory agencies will be demonstrated by reviewing how an understanding of the AOP was used to support arguments that a carcinogenic response with a mutagenic test material could be ascribed to nongenotoxic mechanisms. Collectively, material presented in this session will instill a greater awareness of the value that can be realized with the recent US FDA Biomarker Qualification: Evidentiary Framework and Predictive Toxicology Roadmap initiatives. Although these initiatives were formulated by US FDA, their conceptual underpinnings are universal and applicable for focusing and guiding the dialogue on toxicology issues and concerns with other regulatory agencies, such as the US Environmental Protection Agency. Session attendees will recognize that energetic engagement between industry and regulatory scientists will contribute to the success of the vision of these initiatives and improve decision-making for toxicology, safety assessment, and risk management questions that directly affect human health.
Building Predictive Biomarkers from the Perspective of the Adverse Outcome Pathway. Chris Corton, US EPA/NCCT, Research Triangle Park, NC.
A Roadmap to Innovation in Drug Development—Stories about the US FDA New Biomarker Qualification Program. John Michael Sauer, Critical Path Institute, Tucson, AZ.
Friday, June 19
12:00 Noon–3:30 PM (ET)
PM09 AFTERNOON COURSE
Sven Korte, Covance Preclinical Services GmbH, Germany; and Annette Koerner, F. Hoffmann-La Roche Ltd, Switzerland.
Regulatory and Safety Evaluation Specialty Section
Biotechnology Specialty Section
The field of gene therapy has matured in recent years to bring forward a potential treatment or cure for life-threatening monogenetic diseases. The first successful treatments are already available to patients in various indications, and even more are undergoing active preclinical and clinical development. This CE course aims to summarize the great achievements already established for this promising therapeutic modality, will provide insights into the specific considerations for meaningful preclinical safety assessments, and will introduce the regulatory framework, as well as looking into advancements in the field opening up new opportunities and challenges. This CE course will start with a review of the history of adeno-associated virus (AAV) vector development and give a current status of its clinical use and challenges. A number of unique considerations need to be addressed when designing a nonclinical safety assessment program for AAV gene therapies (GTs), including the off-target tissue distribution and transgene expression, persistence, and immunogenicity. Additionally, although AAVs are generally considered nonintegrating, the potential implication, if any, of a low frequency of integration is not yet well understood. Attendees will hear an overview of preclinical safety assessment strategies for AAV gene-based therapies, including dose extrapolation for first-in-human starting dose, and learn about AAV screening approaches in nonhuman primates (NHPs) and case studies of regulatory-accepted toxicity studies via the oral, IV, and subretinal routes. In addition, a case study of the biodistribution and toxicity profile of an occular AAV gene therapy administered by intravitreal injections (IVT) will be shared. The course will expand into questions on impurity profiling of the drug product and conclude with an overview of the regulatory guidelines for GTs and the sharing of regulatory experience in the field. Take advantage of the renowned group of speakers coming together in this course to share their experience in and deep insight of the field of gene therapy with safety specialists from academia and the pharmaceutical industry, as well as regulatory risk assessment experts. This course offers a rare chance to receive guidance in this emerging and promising scientific area and learn about and discuss its particular challenges.
Introduction to AAV Gene-Based Therapies: It’s All about the Dose. Joy Cavagnaro, Access BIO L.C., Boyce, VA.
Nonclinical Safety Assessment Considerations for AAV-Based Gene Therapies. Kelly Flagella, Ultragenyx Pharmaceutical, Novato, CA.
Specialized Subretinal or MRI-Guided Brain Delivery in Cynomolgus Monkeys. Sven Korte, Covance Preclinical Services GmbH, Münster, Germany.
Intravitreal Delivery of AAV2-Based Vectors—Improved Transduction in Nonclinical Biodistribution and Toxicity Studies. Lutz Mueller, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Preclinical Development of AAV-Based Gene Therapy Products: US FDA/CBER Considerations. Gaya Hettiarachchi, US FDA/CBER, Silver Spring, MD.
Friday, June 26
12:00 Noon–3:30 PM (ET)
AM05 MORNING COURSE
Andrew Gow, Rutgers, The State University of New Jersey; and Angie Groves, University of Rochester Medical Center.
Inhalation and Respiratory Toxicology Specialty Section
Comparative Toxicology, Pathology, and Veterinary Specialty Section; Computational Toxicology Specialty Section
There are a variety of techniques available for assessment of the effect of toxicants upon the lung. One of the most powerful techniques available is the measurement of lung function. There have been a number of both conceptual and technical advances made in recent years in the assessment of lung function, particularly with respect to airway dynamics. However, for many toxicologists, lung function assessment is unclear and the possibilities for its use remain underutilized. The purpose of this clinical education course is to examine the fundamentals that underlie lung function testing and consider in what ways they can be measured and how these data can be related to toxicological outcomes. The first presentation will introduce the concept of lung function and how it has developed with newer technologies, in particular relating structure with function and how modeling can play a part in assessing this relationship. The second presentation will present an overview of lung mechanics. The physiological elements that make up the measurable units of lung function and how pressure and flow data can be used to generate models of lung function to assess toxicological outcomes will be discussed. The third presenter will describe the challenges of measuring lung function and the various approaches that are available to the investigator. The presentation will concentrate on parameters that can be extracted from different measurement techniques and how they can be utilized to gain information about the physiological elements of the lung. This information will be of critical importance to the practicing toxicologist. The fourth presenter will present on feed forward modeling of lung function and how both pathological and physiological data can be combined. He will focus on how animal scale function data can be used to understand the consequences of toxicant exposure to humans. The final presenter will provide a detailed example of how imaging data can be used to predict lung function. The focus of the presentation will be the longitudinal analysis of whole animal in vivo imaging data following toxicant exposure and its relationship to outcome. This technique provides a novel paradigm for assessing the continuous effect of toxicological exposure in the lung. Overall, these presentations will provide the audience with a practical understanding of lung functional data within the context of disease models as well as an understanding of how it can be used to further their own research.
Horses for Courses: Choosing the Right Model for Your Toxicant. Angela Groves, University of Rochester Medical Center, Rochester, NY.
Lung Mechanics: Linking Structure to Function. Jason H. Bates, University of Vermont, Burlington, VT.
Measuring Lung Function at the Preclinical Level. Annette Robichaud, SCIREQ Scientific Respiratory Equipment Inc., Montreal, QC, Canada.
Function-Based Experimental Design: From Hypothesis to Measurement Protocol. Christopher Massa, Columbia University, New York, NY.
Combination of Functional Testing with Lung Imaging to Generate Continuous Response Models. Alexa Murray, Rutgers, The State University of New Jersey, Piscataway, NJ.