Ex vivo therapy of PAH utilizing hiPSC derived ECs in a SuNx PAH Rat model and development of an organ specific BMPR2 KO animal model in rat and pig

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Pulmonary arterial hypertension (PAH) is a progressivevasoconstrictive disease. Due to missing curative therapy options, ithas a 5-year mortality up to 50%. Based on the first funding periodone major goal of the current project is to finally establish the new,innovative therapy concept, which bases on the replacement of thedysfunctional pulmonary endothelial cells by (functionalized) hiPSCderived endothelial cells in an ex vivo lung perfusion system (EVLP).This cellular ex vivo therapy will be evaluated on the one hand in thesugen/normoxic PAH rat model, established in the first funding period.As current animal models do not represent the impact of loss offunction mutations in the BMPR2 gene, which can be detected in 70%of the patients with familial PAH, this clinically relevant BMPR2 knockout (KO) PAH rat model will be developed and established to be usedfor evaluation of the cell therapy concept. Therefore, by directtargeting of the pulmonary endothelial cells in the EVLP the BMPR2KO –PAH model in rats and in pigs will be investigated for thegeneration of clinically relevant data. In the EVLP innovative geneediting methods will be combined with non-integrating viral vectors toachieve a targeted KO of the BMPR2 gene in the pulmonaryendothelium. Besides the detailed characterization of the PAHphenotype in the BMPR2-KO model compared to the well-establishedsugen/normoxic model the effect of the ex vivo cell therapy will beevaluated in both animal models. Detailed comparison of treatmenteffects in both animal models will allow to draw inter alia conclusionswith respect to the underlying mechanisms for PAH development. Inaddition, the newly established ex vivo gene editing will be utilized toinduce a BMPR2 KO in the pulmonary endothelial layer of pig lungs togenerate a PAH large animal model to allow for further translationaldevelopment of the established cell therapy concept.