by Mark Johnson, M.S. Senior Director of Surgery
Classically, pharma, biotech, and device researchers have relied on rodent models to discover and validate disease targets and mechanisms, as well as for the preclinical development of therapeutics. However, the biology of rodents often fails to accurately predict outcomes in patients – perhaps not surprisingly, as mice are not simply miniature people, but have differences in immune function, lifespan, hematological function, regenerative capacity, and environment (sterile and controlled versus complex and dirty). This lack of translational validity has contributed, in part, to the high failure rate for drug development, particularly in the expensive clinical stage. The use of models in larger animals can help address some of these differences between rodents and human, particularly in cardiovascular disease.
The physiological and pathophysiological responses of the swine are similar to humans. Similarities in the major organ systems, the vascular system, gastrointestinal tract morphology, as well as similarities in pharmacokinetics make the swine a better model system for studying cardiovascular disease. In particular, porcine models have been particularly valuable in assessing myocardial infarction and congestive heart failure, as they reflect the human disease state and can be modified to address different research goals. For example, the treatment of myocardial infarction relies on the stabilization of vulnerable atherosclerotic plaques, methods to restore blood flow to affected tissues, and mechanisms to protect ischemic tissue or improve regeneration after ischemia. There are multiple challenges in creating and maintaining consistent plaque formation, and consistently modeling the rupture of those plaques can also be extremely challenging. However, porcine models of atherosclerosis/ischemia or ischemia reperfusion allow examination of interventions on neovascularisation, functional recovery, biomarker changes, vascular remodeling, and infarct size, providing insight into the therapeutic potential of the therapy.
Of course, no single model perfectly duplicates the complexity of human disease, and adding studies to a preclinical development strategy requires consideration of timelines, cost, infrastructure, and the requirement for specialized technical personnel. MPI Research has established swine models of myocardial infarction and congestive heart failure, and has used these models to cost-effectively and quickly assess modalities from small-molecule therapeutics to biologics, devices, and stem cell regenerative therapies. Incorporating these larger animal models earlier into preclinical development plans can contribute to better translation and clinical outcomes.