Fibrotic Disease
Tissue remodeling and scarring is part of the normal wound healing process. Repeated injury and insult, however, can lead to persistent and excessive scarring and, ultimately, organ failure. CTGF is implicated in epithelial to mesenchymal transition (EMT), a cellular process that creates myofibroblasts, which drive scarring. EMT is a final common pathway that underlies all forms of chronic fibrosis.
CTGF Drives Fibrosis
Fibrosis refers to the excessive and persistent formation of scar tissue, which is responsible for morbidity and mortality associated with organ failure in a variety of chronic diseases affecting the lungs, kidneys, eyes, heart, liver, and skin. There are no therapies on the market today that have been shown to arrest or prevent fibrotic disease.
The understanding of CTGF-induced pathology has evolved for more than a decade, beginning in the 1990’s with numerous studies implicating CTGF in chronic fibrosis of multiple organs and tissues, such as kidneys lungs, and skin. More recently, scientific discoveries are revealing the molecular and cellular mechanisms underlying CTGF’s role in fibrosis, for example, CTGF’s critical role in epithelial to mesenchymal transition (EMT).
EMT is a cellular process that transforms normal functioning cells into myofibroblast cells, which produce components of scar tissue. In the normal process of tissue repair, EMT promotes healing of tissues and is shut down once healing has occurred. However, recurring insult and injury, such as that which occurs in chronic disease, results in an imbalance of growth factors (elevated levels of CTGF) and dysfunctional signaling, leading to persistent EMT. Research shows that CTGF drives EMT occurring in multiple types of tissues including kidney, lung, and liver.
Potential for Reversal of Fibrosis
The process of tissue repair is complex, and it has been known for some time that healing can be regenerative or scar forming. It is now appreciated that permanent scar takes a very long time to develop and the process is dynamic. There is an increasing acceptance that fibrosis, as a derivative of this process, is also dynamic and therefore amenable to reversal. Thus, targeting a key participant such as CTGF to achieve a state favoring regenerative repair should provide opportunity to not only beneficially influence outcome in repair, but also to affect reversal of fibrosis.
New data are emerging in support of this point. FibroGen and collaborators have shown in the rodent kidney that CTGF impairs, or contributes to the loss of, the activity of bone morphogenic protein-7 (BMP-7), an important antifibrotic and proregenerative repair factor. Thus, restoration of BMP-7 signaling via CTGF blockade represents a newly appreciated potential mechanism through which fibrosis reversal could occur. In fact, studies in which CTGF activity is experimentally blocked show that EMT can be inhibited in kidney cells and that arterial stiffness can be reversed in diabetic cardiovascular disease models.
Anti-CTGF Development Programs in Fibrosis
FibroGen believes that FG-3019, a fully human monoclonal antibody against CTGF, has the potential to address a number of fibrotic diseases and is has active development programs in the following areas:
Related Publications
Nguyen TQ, et al. (2008) CTGF inhibits BMP-7 signaling in diabetic nephropathy. J Am Soc Nephrol. 2008 Jul 16. [Epub ahead of print]
Burns WC, et al.(2007) The role of tubular epithelial-mesenchymal transition in progressive kidney disease. Cells Tissues Organs. 2007;185(1-3):222-31. Review.
Langsetmo I, et al. Anti-CTGF human antibody FG-3019 prevents and reverses diabetes-induced cardiovascular complications in streptozotocin (STZ) treated rats. Diabetes®, Vol. 55, Suppl.1, 2006; A122.
