Human Genetic Disease Modeling and Physiology Core

Core B - Project Summary To have successful therapies for Alpha-1 antitrypsin deficiency it is necessary to have animal models that recapitulate the phenotypes see in human patients to test therapeutics, including gene therapy and genome editing approaches, and develop clinically relevant therapeutic benchmarks to ascertain the success of those therapies. To that aim this Core is working with Project 1 (Flotte) to create an AAT-Null or PiZ ferret that conditionally expresses human AAT (hAAT) as well as a murine model of the PiZ mutation on the background of the AAT knock-out mouse created in our group. The knock-out mouse recapitulates a lung phenotype with its complete lack of AAT production, but does not completely model the state of the PiZ AAT patient who have some residual blood levels of AAT that produce residual anti-elastase activity. In this Core we aim to create and characterize an AAT-KO-PiZ mouse on the AAT-KO background and well as characterize an existing AAT-KO/PiZ cross mouse. In addition to being a more relevant model to test gene therapies, the AAT-KO-PiZ mouse will also serve as the model to further investigate genome editing of the Z-AAT alleles in Project 2 (Xue). The current PiZ mouse contains multiple copies of the PiZ gene, making it a non-ideal model for genome editing. Both mouse models will allow us to elucidate further the role that the PiZ mutation plays without the presence of wild-type murine AAT, something that has not been modeled in the mouse before. In Core B we will also produce humanized liver NSG-PiZ mice to select for AAV serotypes that target human hepatocytes for Project 3 (Wang). In addition to the production of mouse and ferret models for use in Projects 1, 2, and 3 we will also work with Projects 1 and 2 to characterize the pulmonary phenotype responses to gene therapy and genome editing. The core will offer novel expertise in rodent pulmonary function testing, bronchoalveolar lavage testing and facilitation of lung computed tomography in collaboration with Dr. Bankier and Tufts Cummings School of Veterinary Medicine.