?lpha-1 antitrypsin (AAT) deficiency (AATD) and Chronic Obstructive Pulmonary Disease (COPD) are lung diseases, both of which share phenotypic features, including airflow obstruction and airway mucociliary dysfunction, attributed primarily to emphysema, a condition that defines damage and enlargement of the air sacs of the lungs, causing breathlessness . AATD is the major genetic cause of early-onset COPD, typically exacerbated by cigarette smoking. There is still no cure for AATD/COPD-associated emphysema; no treatment can reverse the damage to the lungs. Prevalence of COPD is increasing significantly, warranting need for new therapies. Lack of a proper animal model that mimics the human disease has been a constraint, owing to structural and functional differences between human and rodent lungs. We propose that pigs with a genetic model of emphysema, in conjunction with exposure to cigarette smoke (CS) could provide consistent pulmonary tissue alterations that are characteristic features of AATD/COPD. This swine model will be of great value for pre-clinical research and facilitate development of innovative treatments to slow, stop or reverse the damage to the lungs caused by AATD/COPD. For that, we plan to generate pigs with AATD, the only defined, genetic risk factor of emphysema. AATD is caused by a mutation of the protease inhibitor (PI) gene, resulting in a reduced level of AAT in blood and lung, leading to breakdown of the lung tissue by the enzyme neutrophil elastase. We intend to utilize our novel gene-editing platform to develop swine with the most prevalent and severe AATD genotype, PI*ZZ. Accordingly, the pig model with the PI*ZZ mutant genotype will develop emphysema, a characteristic feature of AATD PI*ZZ mutant genotype will be exposed to CS to intensify the AATD phenotype to COPD. PI*ZZ . Then, this Realization of this mutant genotype will be monitored by serological testing in vivo, while progression of emphysema is evaluated clinically and confirmed pathomorphlogically. We believe that such a reliable large animal model of AATD/COPD- linked emphysema will have tremendous impact on industry and academic research to develop and test new drugs and novel therapeutic approaches to treat AATD/COPD-associated emphysema.
Emphysema is a classic feature of lung diseases , ?lpha-1 antitrypsin (AAT) deficiency (AATD) and Chronic Obstructive Pulmonary Disease (COPD). This SBIR aims to develop a swine emphysema model using gene- editing to mimic the most common and severe allele of AATD (PI*ZZ mutation) observed in human patients. These gene-edited pigs will be exposed to the major cause of COPD, cigarette smoke, to simulate both genetic and environmental risk factors. There is still no cure for AATD/COPD-associated emphysema, no treatments proven to reverse the damage to the lungs, and without transplant, all patients' progress into severe pulmonary failure. We propose that this unique large animal model will more accurately mimic the human condition and accelerate translation of novel therapies into the clinic.
