Unleashing innovative cross-organ fibrosis therapies by harnessing the omics revolution

Figures

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  Figure 1. The feed-forward cycle of injury, inflammation, differentiation, and scarring in chronic fibrotic disease. Chronic fibrotic diseases across organs are driven by a conserved, self-perpetuating cycle of injury, inflammation, cell differentiation, and scarring. An insult (e.g., environmental toxins, pathogens, genetic predisposition) begins the cycle. Insult leads to injury via cellular stress that activates the endoplasmic reticulum unfolded protein response (UPR), releases alarmins and mitochondrial reactive oxygen species, and culminates in epithelial cell death. These events initiate the inflammatory phase due to platelet infiltration, recruitment of innate immune cells (e.g., monocytes/macrophages, neutrophils, dendritic cells, DCs), and activation of adaptive immune responses (Th2 cells, Th17 cells, Tregs, B cells), orchestrated primarily by a milieu of type 2 and type 3 cytokines. This immune activation induces the loss of tissue homeostasis and primes the fibrotic niche. During the differentiation phase, endothelial cells undergo defenestration with loss of endothelium integrity and a switch to a pro-inflammatory/recruitment phenotype, while resident macrophages are depleted…

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  Figure 2. Representative overview of existing and novel therapeutic modalities. Therapeutic modalities are organized from small (left) to large (right) molecules. Untargeted therapeutics are located on the top side of the figure while the bottom part represents cell-specific modalities. Each light color shading represents a specific modality: small molecules (blue), oligos (yellow), peptides (pink), large molecules (red), and cell depletion strategies (purple). Watercolor overlap highlights therapeutics combining different modalities, such as antibody drug-conjugate (ADC) or antibody oligo-conjugate (AOC). Nanoparticles deliver both small molecules and oligos can be further directed to relevant cell types when combined with a targeting arm (green). The left and right gradients show the relative impact (blue low, red high) of phenotypic omics and perturbation screen on the discovery of novel therapeutic targets (top) versus cell-targeting strategies (bottom).