Strategies to overcome the hurdles to treat fibrosis, a major unmet clinical need

Fibroproliferative disorders are estimated to contribute to 45% of deaths in the United States (1). Although this huge number includes atherosclerosis, the biggest killer in the developed world, less common conditions, such as idiopathic pulmonary fibrosis, fibrosis of the liver and kidney, and systemic sclerosis are also associated with high mortality. Localized fibrotic conditions—including endometriosis, abdominal adhesions, frozen shoulder, and Dupuytren’s disease—which receive much less attention, also cause considerable morbidity and together affect more than 10% of the population.

The magnitude of this unmet clinical need has resulted in intense efforts to develop novel therapeutic strategies. Despite this effort, success remains elusive for a multitude of reasons. (i) Detection: Fibrosis is the end stage of a process that develops over many years—often decades—and patients usually present late, once organ function has been significantly compromised. Early predictors and biomarkers are scarce. (ii) Reversibility: Elimination of the initiating insult, such as hepatitis B viral infection, results in regression of fibrosis and restoration of function in the liver (2). However, in the majority of organs and even other liver disorders, such as nonalcoholic steatohepatitis, this process is irreversible. (iii) Matrix: Late-stage fibrotic tissues are relatively acellular, leaving few cells to target and a densely cross-linked matrix that is barely susceptible to proteolysis. (iv) Tissue availability: The study of primary cells from diseased human tissues has proven to be highly successful in the identification of therapeutic targets, as exemplified by TNF in inflammatory arthritis (3). In fibrotic diseases, human samples are available in very limited quantities and, even when they can be accessed, have failed to provide insights that have translated to successful clinical trials. (v) Cell and animal models: Consequently, investigators have turned to the study of cells in culture to identify and study potential new targets in fibrosis. The main effector cells …

↵¹To whom correspondence should be addressed. Email: jagdeep.nanchahal{at}kennedy.ox.ac.uk.