Antitransforming growth factor-β therapy in fibrosis: Recent progress and implications for systemic sclerosis

John Varga*, Boris Pasche

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

71 Scopus citations

Abstract

Purpose of review: Transforming growth factor-β (TGF-β) is required for tissue homeostasis but is also implicated in disease processes including fibrosis, and thus represents a molecular target for therapy. Recent findings: Multiple strategies for inhibiting excessive TGF-β function exist. The three principal platforms are RNA-based technologies, monoclonal antibodies and small molecules. Monoclonal antibodies targeting TGF-β have been used in a small clinical trial, with disappointing results to date. Antibodies to the αvβ6 integrin prevent local activation of latent TGF-β and show promise in preclinical studies. Over a dozen small molecules inhibit the kinase activity of TGF-β receptors. Several commonly used drugs appear to have unanticipated anti-TGF-β activity and may therefore have a role in antifibrotic therapy. Because TGF-β has important physiological functions, inhibiting its activity might potentially lead to aberrant immune activation, epithelial hyperplasia and impaired wound healing; spontaneous autoimmunity in particular is a concern in an autoimmune disease such as systemic sclerosis. Novel insights from DNA microarray analysis and genetic polymorphisms in TGF-β signaling will aid in defining patient populations most likely to respond to anti-TGF-β treatment. Summary: Anti-TGF-β therapies promise to have a major impact in systemic sclerosis. Significant concerns regarding efficacy and safety need to be addresed. The identification of optimal candidates for therapy, and of biomarkers of safety and efficacy, are critical challenges ahead.

Original languageEnglish (US)
Pages (from-to)720-728
Number of pages9
JournalCurrent opinion in rheumatology
Volume20
Issue number6
DOIs
StatePublished - Nov 2008

Keywords

  • ALK5
  • Fibrosis
  • Scleroderma
  • Therapy
  • Transforming growth factor-β
  • avβ6 integrin

ASJC Scopus subject areas

  • Rheumatology

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