Pharmacological Treatment of Fibrosis: a Systematic Review of Clinical Trials

SN Comprehensive Clinical Medicine (2020) 2:531–550 https://doi.org/10.1007/s42399-020-00292-2 MEDICINE Pharmacological Treatment of Fibrosis: a Systematic Review of Clinical Trials Alessandro Siani 1 Accepted: 16 April 2020 / Published online: 4 May 2020 # The Author(s) 2020 Abstract The term “fibrosis” refers to a spectrum of connective tissue disorders characterized by the excessive accumulation of extracellular matrix leading to organ dysfunction and, ultimately, failure. Fibrosis affects millions of patients worldwide and often manifests itself as a late-stage pathological condition associated with poor prognostic outcome. Although the aetiology and clinical course vary widely depending on the affected organ, fibrotic degeneration of different tissues is underpinned by similar molecular and cellular mechanisms, most notably the persistence and dysregulated activity of myofibroblasts. A systematic search of clinical trials was conducted using PubMed and Cochrane to qualitatively evaluate the effectiveness of different therapeutic approaches to the pharmacological targeting of myofibroblasts in patients affected by fibrotic disorders. The systematic search and screening returned 54 eligible clinical trials, 38 of which reported an improvement of the patients’ symptoms following treatment. The majority of the eligible articles focused on fibrotic degeneration of the respiratory system, skin, liver, and kidneys. The evaluation of clinical data unearthed commonalities between strategies that successfully ameliorated symptoms in patients affected by the same fibrotic disorder. However, none of the treatments evaluated in this study could improve symptoms across a range of fibrotic pathologies. These results indicate that, although no “one size fits all” treatment for fibrosis has yet been identified, the systematic analysis of clinical data can be used to inform the development of therapeutical strategies tailored to suit the diverse aetiology of each fibrotic condition. Keywords Fibrosis . Myofibroblasts . Treatment . TGF-β . Extracellular matrix . Clinical trial Introduction Background and Rationale of the Study Despite extensive investments and research efforts, no such thing as a “cure for fibrosis” has been as of yet discovered, and replacement of the affected organ remains the most frequent treatment strategy. There are several factors that render fibrosis treatment a challenging matter [1]. Aside from its inherently heterogeneous nature (i.e. it is not a distinct pathology, but rather an umbrella term covering a wide spectrum of conditions), fibrosis often represents a pathological end-state, and in This article is part of the Topical Collection on Medicine * Alessandro Siani 1 School of Biological Sciences, University of Portsmouth, King Henry Building, King Henry 1st Street, Portsmouth PO1 2DY, UK most cases, it is only diagnosed after tissue degeneration has already taken place to a significant extent. Moreover, the increased deposition of highly cross-linked extracellular matrix (ECM) represents a significant physical barrier to the delivery of therapeutical agents to the affected tissue. As mentioned in the previous section, clinical intervention is further complicated by the self-sustaining nature of myofibroblasts that, by secreting profibrotic cytokines and generating tensile force, produce a local environment permissive to the persistence and propagation of fibrosis [2]. Given their fundamental role in the onset and progression of fibrosis, myofibroblasts are considered appealing pharmacological targets [3]. An increasing body of experimental evidence (summarized in Table 1) seems to indicate that the cytokines basic fibroblast growth factor (bFGF or FGF2), transforming growth factor β3 (TGF-β3), interferon γ (IFN-γ), and interleukin-1 (IL-1) are appealing candidates for the pharmacological targeting of myofibroblasts [4]. While there indeed are several other compounds that have been shown to regulate myofibroblast activity in a preclinical 532 Table 1 SN Compr. Clin. Med. (2020) 2:531–550 Preclinical evidence on the antifibrotic effect of the cytokines bFGF, IFN-γ, TGF-β3, and IL-1 Ref Treatment Model Outcome [27] FGF-2 (bFGF) Wistar rats ↑ Myofibroblast apoptosis ↓ α-SMA expression [28] FGF-2 (bFGF) Porcine valvular interstitial cells ↓ α-SMA expression ↓ TGF-β1 signalling ↓ Contraction [29] FGF-2 (bFGF) Porcine dermal cells ↓ α-SMA expression ↓ Cell spreading [30] FGF-2 (bFGF) Wistar rats ↑ Myofibroblast apoptosis ↓ α-SMA expression [31] FGF-2 (bFGF) Human adipose-derived mesenchymal stem cells ↓ Cell spreading ↓ α-SMA expression [32] FGF-2 (bFGF) C57BL/ksJ db/db mice ↑ Myofibroblast apoptosis ↓ Scarring [33] FGF-2 (bFGF) New Zealand rabbits ↓ Scarring ↓ α-SMA expression [34] FGF-2 (bFGF) Human cardiac myofibroblasts ↓ Contraction ↓ TGF-β1 signalling ↓ ECM remodelling ↓ Cell spreading [35] IFN-γ Human skin fibroblasts and wound healing myofibroblasts ↓ Contraction ↓ α-SMA expression ↓ Total collagen production [36] IFN-γ Wistar rats ↓ Scarring ↓ α-SMA expression ↓ Collagen III and IV expression [37] IFN-γ Rat hepatic stellate cells ↓ α-SMA expression ↓ Proliferation ↓ Collagen I and IV expression ↓ Fibronectin expression [38] IFN-γ Rat hepatic stellate cells ↓ α-SMA expression ↓ Proliferation [39] IFN-γ knockout C57BL/6 mice ↑ TGF-β1 expression ↑ α-SMA expression [40] IFN-γ Wistar rats ↓ Myofibroblast density ↓ Collagen III expression ↓ Hydroxyproline content [41] IFN-γ Human gingival fibroblasts and myofibroblasts ↓ α-SMA expression ↓ Collagen I expression ↓ Cell spreading [42] IFN-γ WI-38 human fibroblasts ↓ α-SMA expression [43] IFN-γ Rat palatal fibroblasts ↓ α-SMA expression ↓ Proα2(I) collagen expression ↓ Contraction [44] IFN-γ Human foetal lung fibroblasts ↓ α-SMA expression ↓ Cell spreading [45, 46] IFN-γ (free and PEGylated) C57BL/6 mice; NIH3T3 mouse fibroblasts ↓ Hydroxyproline content ↓ α-SMA expression SN Compr. Clin. Med. (2020) 2:531–550 533 Table 1 (continued) Ref Treatment Model Outcome ↓ Fibronectin expression ↓ Collagen I and III expression [47] IFN-γ C57BL10J+/+ mice; muscle-derived fibroblasts ↓ Total collagen production ↓ α-SMA expression [48] TGF-β3 Wistar rats; human dermal fibroblasts; rat dermal fibroblasts ↑ Total collagen production (in vivo) ↑ α-SMA expression (in vitro) [49] TGF-β3 Sprague-Dawley rats ↓ Scarring ↓ Fibronectin expression ↓ Collagen I and III expression [50] TGF-β3 Human corneal fibroblasts (3D culture) ↓ Collagen III expression ↓ α-SMA expression [51] TGF-β3 transduction CD1 mice; murine dermal fibroblasts ↓ α-SMA expression ↓ Scarring [52] TGF-β3 CL/Fraser mice ↓ Scarring ↓ Collagen I expression ↓ α-SMA expression [53] TGF-β3 C57BL/6 mice; human keloid fibroblasts ↓ α-SMA expression ↓ Collagen I expression ↓ Scarring [54] IL-1α Human fibroblast/keratinocyte co-culture ↓ α-SMA (...truncated)