W. Mark Saltzman, PhD
Goizueta Foundation Professor of Biomedical Engineering and Professor of Cellular and Molecular Physiology and of Chemical Engineering; Affiliated Faculty, Yale Institute for Global Health; Department Chair, Biomedical Engineering
Project Title: Ex Vivo Liver Perfusion for Nanoparticle Delivery to Sinusoidal Endothelial Cells
In 2021, over 13,000 people were added to Liver Transplant Waitlist, the largest single year addition. With only 9,500 livers recovered, there is a need to transplant as many livers as possible without risking patient health and safety. Furthermore, around 10% of the recovered livers were declined for transplant, further reducing the already limited supply. Therefore, it is critical to improve the function of as many marginal organs as possible. One issue that is exacerbated in marginal organs is ischemia reperfusion injury (IRI). Current studies have implicated that nitric oxide, derived from endothelial nitric oxide synthase, can have a protective benefit during IRI. In marginal livers, the sinusoidal endothelial cells may have also undergone capillarization. This disease state precedes fibrosis and can result from many different etiologies. A GTPase of the immunity-associated protein family member 5 (GIMAP5) has been shown to be critical in the transition from healthy to capillarized endothelial cells. We hypothesize that it would be useful to exclusively target endothelial cells in the liver while avoiding other cell types to prevent off target effects and toxicities. Ex vivo perfusion (EVP) gives us a unique opportunity to assess targeting exclusively in the liver and is a clinically relevant transplant application. The goal of this proposal is to address IRI and capillarization in endothelial cells during liver EVP using antibody-targeted nanoparticles to deliver nucleic acids.