Scalable Generation of Universal hiPSC-Derived Vascular Progenitor Cells for Safe and Sustained Revascularization in Chronic Limb-Threatening Ischemia

BackgroundChronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease and can result in debilitating tissue damage, limb loss, and mortality if left untreated. Despite surgical bypass and endovascular interventions, there is high unmet need to develop novel therapies that can restore durable blood flow and rescue limb function in patients whose disease is not amenable to surgical bypass and endovascular procedures. Human induced pluripotent stem cell (hiPSC)-derived vascular progenitor cells (VPC) hold promise for addressing this unmet need, yet their clinical adoption will require a scalable and consistently high-quality cell product that can be used safely in a large number of CLTI patients. MethodsHere, we report a robust, scalable GMP-adaptable platform for generating universally immuno-compatible VPC from human leukocyte antigen (HLA) class I/II-edited hiPSCs with extensive characterization of phenotypic and functional attributes critical to address key translational gaps in developing cell-based therapies for CLTI. We have interrogated their therapeutic efficacy in multiple murine CLTI models using a combination of clinically relevant endpoints, histology, and tissue-based RNAseq analysis. ResultsWe found that VPC-treated mice exhibited significantly improved perfusion ratios and preserved limb function, reduced inflammation, and increased physiological neovascularization without pathological malformations. ConclusionsGenetic modification conferring hypoimmune status coupled with a robust differentiation process enables large scale production of an "off-the shelf" high-quality VPC product with the potential to address unmet need in CLTI patients regardless of HLA status.