Recombinetics, Inc. — Department of Health and Human Services SBIR Phase I: 100

Description

PROJECT SUMMARY lpha 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 PROJECT NARRATIVE Emphysema is a classic feature of lung diseases lpha 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 patientsandapos 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