Wednesday, May 8, 2024
5/8/2024
Acute respiratory distress syndrome (ARDS) is a high mortality condition in which the lung epithelium is unable to mount its usual regenerative response to injury. Despite promising preclinical data showing that cell-based therapy, primarily adoptive transfer of mesenchymal stromal cells, can promote epithelial regeneration in acute lung injury, the mechanism behind these findings is unclear, and thus they have not been successful in clinical trials. Currently, there are no mechanism specific treatments for ARDS, even though the COVID-19 pandemic has increased the urgency of the need for ARDS treatments to tackle ongoing and future respiratory pandemics. In this proposal, we aim to develop cell-based therapy using a mechanistic approach with the goal of delivering growth factors that promote alveolar epithelial cell (AEC) proliferation to the injured lung. We will use engineering principles from the CAR T cell field and combine them with knowledge from in vitro and in vivo studies of lung epithelial injury response to develop a potent new model for delivering therapeutics. Hepatocyte growth factor (Hgf) and keratinocyte growth factor (Kgf) are known to stimulate AEC proliferation and protection from lung injury in mouse models and hence we will initially focus on delivering these growth factors as therapeutics. First, we will evaluate in vitro how to best design “sender” engineered T cells to secrete sufficient concentrations of growth factors to activate downstream signaling pathways in “receiver” cell lines or primary lung epithelial cells. Next, we will use mouse models of lung injury to compare delivery of intravenous recombinant Hgf and Kgf vs delivery of these factors via adoptive transfer of T cells. We will then confirm in vitro and in vivo that we can engineer synthetic notch receptors that activate an engineered transcriptional output (“payload”) when they bind to lung epithelium specific surface markers. The surface markers we have selected are membrane GFP expressed specifically on surfactant protein C expressing type 2 AECs (from an SFTPC-CreERT2; H11-lsl- mGFP mouse), Ager, expressed on mouse and human type I AECs, and Slc34a2, expressed on mouse and human type 2 AECs. Finally, we will combine these two systems to engineer T cells that deliver their “payload,” in this case Hgf or Kgf, only when they contact an AEC, thus activating the AEC specific synthetic notch receptor (AEC-SynNotch). We expect that we will see an increase in AEC proliferation after lung injury with adoptive transfer of these AEC-SynNotch-Hgf or AEC-SynNotch-Kgf cells and that we will also see improvements in physiologic and histologic measures of lung injury. The completion of this project will generate data that will provide a clearer understanding of how mechanistically engineered cell-based delivery of a growth factor compares to delivery of the same therapeutic in IV recombinant form. Our long-term plan is to apply these design principles to cells already being used in ARDS clinical trials (mesenchymal stromal cells and regulatory T cells) to improve efficacy, which will represent a new paradigm for designing cell-based therapies to deliver genetically encoded therapeutics to specific tissues.
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