GENETICALLY ENGINEERED PIG MODELS FOR TRANSLATIONAL DIABETES RESEARCH

Abstract

Animal models play crucial roles for understanding disease mechanisms and for the development and evaluation of therapeutic strategies. In biomedicine, classical rodent models are most widely used for several reasons, including standardization of genetics and environment, cost efficiency, and the possibility to introduce targeted genetic modifications for the generation of tailored disease models. However, due to differences in anatomical and physiological characteristics, rodent models do not always reflect the situation of human patients sufficiently well to be predictive in terms of efficacy and safety of new therapies. In this respect, the pig has been discussed as a missing link between mouse models and human patients. As a monogastric omnivore, the pig shares many anatomical and physiological similarities with humans. Importantly, the techniques for genetic modification of pigs have been refined to a level allowing almost the same spectrum of alterations as in mouse models (Aigner et al. 2010 J. Mol. Med. (Berl.) 88, 653–664). These include inducible transgene expression systems (Klymiuk et al. 2012 FASEB J. 26, 1086–1099) as well as the introduction of targeted genetic modifications (Klymiuk et al. 2012 J. Mol. Med. (Berl.) 90, 597–608). A major focus of our laboratory is the generation, characterisation, and implementation of pig models for translational diabetes research. Transgenic pigs expressing a dominant negative receptor for the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) demonstrated a crucial role of the GIP system for the physiological age-related expansion of pancreatic β-cell mass. Moreover, this animal model shares important characteristics of type 2 diabetes mellitus: impaired incretin effect, reduced glucose tolerance and insulin secretion, and a progressive reduction of β-cell mass (Renner et al. 2010 Diabetes 59, 1228–1238). More recently, we used this model to search for metabolic biomarkers which are associated with progression in the pre-diabetic period and identified specific amino acid and lipid signatures as candidate biomarkers (Renner et al. 2012 Diabetes 61, 2166–2175). Further, we created the first pig model for permanent neonatal diabetes by expression C94Y mutant insulin in the β-cells of transgenic pigs. In addition to their use as biomedical models, pigs may also serve as organ and tissue donors for xenotransplantation. Transplantation of encapsulated porcine pancreatic islets to type 1 diabetic patients with severe unaware hypoglycemia has already entered clinical studies, but encapsulation may shorten the lifespan of the islets. Therefore, in order to overcome the rejection of pig islets by human T-cells, we generated transgenic pigs expressing the optimized CTLA-4Ig variant LEA29Y in the pancreatic β-cells. Islets from LEA29Y transgenic pigs rescued diabetes and were protected against rejection in a humanized mouse model (Klymiuk et al. 2012 Diabetes 61, 1527–1532).