Activation of resident mesenchymal cells is a common theme in tissue fibrosis across organs. In liver hepatic stellate cells (HSC) are the primary source of extracellular matrix in normal and fibrotic liver. They undergo an “activation” or transdifferentiation in progressive stages yielding a cell type that is highly proliferative, fibrogenic and contractile; similar cells contribute to fibrosis in kidney, lung and other tissues. Activation of resident pericytes in all tissues is the central event of fibrogenesis, combined with variable recruitment of other mesenchymal cells that also become activated myofibroblasts. The increasing evidence that fibrosis is a dynamic and reversible process, the clarification of the underlying sources and mediators of fibrosis progression, and advances in non-invasively assessing fibrosis have generated enthusiasm towards developing effective anti-fibrotic drugs, although none are approved yet. In reality, there may already be many existing drugs with well-established safety profiles, whose mechanism of action will be also anti-fibrotic even though they have been developed for other indications. Increasingly, such targets for repurposed drugs can be uncovered using high throughput methods combined with ‘big data’ analysis. There are several therapeutic target classes in developing anti-fibrotic agents: Eliminate the cause of injury and their mediators Attenuate hepatocyte injury – ‘Hepatoprotectants’ Reduce inflammation and the immune response Target specific signaling – receptor-ligand interaction, intracellular signaling Reduce fibrogenesis, inhibit matrix synthesis Resolve fibrosis by - Increasing scar matrix degradation - Stimulating apoptosis or reversion of stellate cells - Bone marrow or cell transplantation Regulatory Challenges in Developing Novel drugs A key challenge in the testing of anti-fibrotic drugs is the need for endpoints that are noninvasive, yet correlate well with clinical outcomes. Moreover, in trials that include patients who are clinically stable, reliance on clinical events as a ‘hard’ endpoint is desirable. Stratification of risk for progression should ideally be incorporated into clinical trial design wherever possible. Despite the challenges, increasing cooperation among stakeholders in fibrosis therapeutics development is likely to foster improvements in trial design that accelerate drug approval.

Organ and tissue fibrosis: Principles and prospects for therapy

249th National Meeting (2015)

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