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CD47

CD47 (Cluster of Differentiation 47) is a transmembrane protein found widely on human cells that functions as a receptor for the secreted protein thrombospondin-1 (TSP1) and for cell membrane signal regulatory protein α (SIRPα). TSP1 binds with high affinity to CD47 (~kD 12 pM) whereas CD47 binds SIRPα with much lower affinity. The TSP1-CD47 axis regulates redox signaling by limiting the beneficial effects of the biogas nitric oxide and by stimulating NADPH oxidase-derived superoxide production. This has multiple negative effects upon angiogenesis, wound healing, blood flow, and cardiovascular function. Thus, the TSP1-C47 interaction promotes hypoxia, ischemia, cardiac failure and transplant injury.  

TSP1, via CD47, also limits key self-renewal transcription factors including Oxt3/4, Sox2, Klf4 and cMyc. This leads to suppression of cell growth and stemness. Conversely, removing the TSP1-CD47 signal allows for cells to revert to a pluripotent phenotype. Thus, the TSP1-CD47 axis represents a natural brake upon the so-called Yamanaka factors. 

In the immune system, both the TSP1-CD47 axis and the CD47-SIRPα axis serve as restraints (checkpoints) upon cell activation. While TSP1-CD47 restrains T, natural killer and dendritic cells, CD47-SIRPα primarily suppresses phagocytosis. The actions of these pathways on immune cells have implications for auto-immunity and are being leveraged as cancer therapies. Beyond this, the TSP1-CD47 axis is unique as it is an independent regulator of cell responses to the genotoxic stress of radiation and chemotherapy. Lowering the TSP1-CD47 signal provides protection to normal cells and tissues from high-dose radiation and chemotherapy while rendering cancers more sensitive to the genotoxic stress. 

San Rocco Therapeutics is working with Dr. Jeff Isenberg to develop new therapies that alter CD47 signaling. 

CD47 Morpholino for Beta Thalassemia white paper

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