Integrins are heterodimeric transmembrane proteins that mediate cell-cell and cell-matrix interactions. Indalo is targeting a subset of integrins expressed on epithelial cells and fibroblasts that recognize an Arg-Gly-Asp (RGD) sequence in cognate ligands. Although the upstream insults that drive pathologic fibrosis vary across different diseases, RGD-binding integrins play fundamental roles in perpetuating shared fibrogenic processes.
One role of RGD-binding integrins is the activation of TGF-b, a central regulator of pathologic fibrosis. Historically, integrin programs targeting fibrosis have focused on avb6, which is expressed on epithelial cells, to reduce TGF-b activation (Puthawala et al., 2008).
Fibroblast-expressed integrins, however, are also able to activate TGF-b. Prominent in this category is avb1, the antagonism of which has been shown to provide preclinical antifibrotic activity (Reed et al., 2015). Targeting fibroblast integrins may be particularly critical for addressing fibrosis in NASH.
Furthermore, apart from mechanisms related to TGF-b, RGD-binding integrins play critical roles in the ability of cells to sense and interact with stiff matrix. For example, fibroblast-expressed avb3 has been implicated in both directing fibroblast migration and in mediating a survival signal required by activated, collagen-depositing fibroblasts (myofibroblasts) (Fiore et al., 2018; Jiang et al., 2006; Matter and Ruoslahti, 2001; Zhou et al., 2004). This suggests that targeting RGD-binding integrin roles beyond TGF-b activation may access additional, complementary antifibrotic mechanisms.
Indalo is advancing the scientific frontiers of integrin pathobiology, investigating the breadth of mechanistic roles played by RGD-binding integrins in fibrosis in order to design and develop drug candidates fine-tuned for optimal utility in fibrotic disease.