Swine in Translational Research and Drug Development

Over the past 2 decades, a significant increase in the use of swine in translational research, including nonclinical safety assessment, has led to an enhanced understanding of human diseases and improvements in human health. Advantages of the pig (Sus scrofa) for translational research include a defined genome sequence and similarity to humans in terms of anatomy, physiology, and biochemistry, with the minipig offering the additional advantages of reduced size and decreased time to sexual maturity. An informal literature search (Google Scholar) on the minipig in translational research or nonclinical safety assessment identified more than 500 publications in the last 2 years, indicating the continual and growing interest in swine as an animal model.

Swine have been used as general surgical models and as animal models of human disease for many decades; this includes diabetes mellitus, atherosclerosis, wound healing, and, more recently, uterine fibroids (leiomyomas) and the metabolic syndrome (Mozzachio et al.; Lerman and Xin, this issue). Use of swine, primarily the minipig, in nonclinical safety assessment studies for development of biopharmaceuticals and implantable medical devices is more recent, with Europe leading the way. The 2010 RETHINK report (http://www.rethink-eu.dk, last accessed January 11, 2016) highlighted the potential utilization of the minipig as an alternative approach to traditionally utilized nonrodent animal models in toxicology (i.e., dog and nonhuman primate). The Preclinical Safety Leadership Group (DruSafe) of the International Consortium for Innovation and Quality in Pharmaceutical Development conducted a survey to provide an updated assessment of the utility, perceived value, and impediments to the use of the minipig in preclinical safety testing. They concluded that the minipig is a viable nonrodent model for development of small molecules and dermal products but that its use has not substantively increased since the last industry survey conducted over 5 years ago (Colleton et al. this issue). This issue of Toxicologic Pathology highlights the latest developments in the utilization of swine in translational research with an emphasis on toxicological pathology and nonclinical safety assessment. The pros and cons of using the minipig in drug development (Heining and Ruysschaert), gaps for using the minipig for safety assessment of biologicals (Kammuller et al.) and anticancer therapeutics (Mahl et al.), and a review of the amount of test article needed to conduct toxicology studies (Schaefer et al.) are also addressed in this issue. Since the pathologist plays an integral role in the diagnosis and interpretation of data generated from these swine models, a major portion of the issue is devoted to the generation and interpretation of pathology data.

Genetically engineered pigs have become increasingly recognized as valuable models for the study of human diseases. New technologies, such as the precise gene editing technology CRISPR/Cas, hold great promise in more efficient and precise development of animal models to investigate the pathogenesis and treatment of human disease (Klymiuk et al.; Redel and Prather this issue). Engineered swine models of human disease include cystic fibrosis, Duchenne muscle dystrophy, combined immunodeficiency (Klymiuk et al.; Redel and Prather this issue), and atherosclerosis (Amuzie et al. this issue). As the evaluation of cellular markers becomes an important component of determining the translational relevance of these novel models, Meyerholz et al. (this issue) compare multiple immunohistochemical markers across the pig and human lung while Atzpodein et al. (this issue) optimize immunohistochemistry and in situ hybridization biomarkers for the pig eye.

Imaging modalities, such as computed tomography and magnetic resonance imaging, utilized both in translational research and toxicology studies, can provide noninvasive assessment of structure and function in “real time,” longitudinally, over the duration of a study. These beneficial characteristics can supplement studies in swine by mirroring the clinical functions of detection, diagnosis, and monitoring in humans. In this issue, Hammond and coworkers present methods for pulmonary imaging in a pig silicosis model that can be correlated to a more traditional histopathology evaluation, while Atzpodien et al. adapt optical coherence tomography for longitudinal assessment of ocular toxicity in the pig.

As mentioned previously, the pathologist plays an integral role in evaluating animal models of disease and in nonclinical safety assessment. To optimize these evaluations, appropriate sample collection (Blutke et al. this issue), standardized nomenclature, and appropriate interpretation of tissue changes are essential. A database of potential histopathological background observations in the pig is needed to assist in identification of test article and treatment-related changes in the interpretation of tissue alterations. In this issue, a wide range of background data is presented by both Helke et al. reporting on a collaborative effort between multiple organizations in North America and the European Union and by Stricker-Krongrad et al. providing control clinical and anatomic pathology data from a large number of breeds including Sinclair, Hanford, Yucatan, and Göttingen. In addition, infrequent spontaneous observations and potential artifacts in the Göttingen minipig are presented (McInnes and McKeag this issue). Finally, an update on the status of the International Harmonization of Nomenclature and Diagnostic Criteria initiative in regard to the minipig, which will be used for the standardized nonclinical data submission to the U.S. Food and Drug Agency, is included (Skydsgaard this issue).

In summary, this issue of Toxicologic Pathology reviews the current knowledge, recent advances, and future potential of swine in the field of translational research and drug development. In addition, information relevant to the pathologist involved in evaluating animal models of human disease and in nonclinical safety assessment has been included. This information will provide readers with a current perspective and increase confidence in extrapolation of data from the pig model to human disease and risk assessment. Since the field cannot be covered in a single issue, we recommend that the readers make use of the references provided in the individual articles and the literature to further explore the field. We hope this issue will be of interest to basic researchers, veterinary and toxicologic pathologists, comparative and translational scientists, and toxicologists working in the biomedical community.