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Lost In Translation: The Use of Large Animal Disease Models in Preclinical Research

April 6, 2015

Animal models of human disease have been used for decades by the pharmaceutical industry to confirm “proof-of-concept” for a molecular target or to evaluate the efficacy of new chemical entities or toxicity of a certain compound when used to treat the underlying condition.  Yet, for the medical device research and development community, the transition of these disease models into large animals has been neither widely adopted nor successful.  There are a number of factors that have accounted for this:

 

     1.  The models do not mimic the pathophysiology seen in the clinic.

     2.  The creation of the model is cost prohibitive.

     3.  The time needed for the onset of the disease is not feasible.  

However, barriers to the development of quality animal models of disease are constantly being broken down. For instance, genetic modification, once a technology that was only available in rodents and zebrafish is now readily available in large animals such as swine (www.exemplargenetics.com). These models can be used for the evaluation of both medical devices and pharmaceutical agents.  Exemplar Genetics, a collaborative partner of APS, is able to develop a variety of disease models through its gene modification technology and model production system.  They are currently active in developing animal models of heart disease, cystic fibrosis, cardiac arrhythmia, cancer, neuromuscular disorders, neurodegeneration, and immunodeficiency.  Specifically, a model of inducible soft tissue cancer has been characterized that can allow evaluation of tumor-imaging diagnostics, surgical- or device-mediated tumor debulking, pharmacological treatment using small molecules or biologicals then follow-up radiation therapy and imaging for long term monitoring; routine clinical practices which were never available in traditional rodent tumor models.

Another example is the work currently being done at APS.  In addition to our expertise in small animal pain models, we have developed a number of large animal disease models to be used in the investigation of medical devices.  One example is a model of calcified vascular lesions.  This model is designed to mimic a calcified atherosclerotic plaque and exhibit similar physical properties to those observed in the clinic.  This bone marrow plug is placed interventionally, either in the coronary or peripheral arteries, to simulate the properties of a calcific chronic partial occlusion (CPO) or a chronic total occlusion (CTO).  These lesions can then be used for the evaluation of percutaneously delivered technologies and therapies.

Baseline OCT Lesion of Left Femoral Artery

       Baseline OCT Lesion of Left Femoral Artery

At APS, we have a variety of animal models of disease in species ranging from mice to sheep, involving neurological, orthopedic, metabolic, and cardiovascular diseases. If you are interested in learning more about large animal disease models, please contact Dr. Mark Smith at 763-951-8046 or Michael Frie at 763-951-8066.