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The Proceedings of the American Thoracic Society 3:389-393 (2006)
© 2006 The American Thoracic Society

Targeting Genes for Treatment in Idiopathic Pulmonary Fibrosis

Challenges and Opportunities, Promises and Pitfalls

Kjetil Ask, Gail E. M. Martin, Martin Kolb and Jack Gauldie

Department of Pathology and Molecular Medicine, Center for Gene Therapeutics; and Department of Medicine, Firestone Institute for Respiratory Health, McMaster University, Hamilton, Ontario, Canada

Correspondence and requests for reprints should be addressed to Jack Gauldie, Ph.D., Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada L8N 3Z5. E-mail: gauldie{at}mcmaster.ca

ABSTRACT

The currently accepted approach to treatment of idiopathic pulmonary fibrosis (IPF) is based on the assumption that it is a chronic inflammatory disease, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in IPF aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of IPF has largely come from the use of animal disease models in rodents. Most data suggest, from among the different factors, a prominent role for the transforming growth factor (TGF)–ß1 and platelet-derived growth factor pathways. Inflammation is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-ß and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.

Key Words: pulmonary fibrosis • targeting genes • therapeutics review

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive disease of unknown origin, characterized by extensive accumulation of collagen and other extracellular matrix, resulting in irreversible loss of pulmonary function. Life expectancy after diagnosis varies, but is on average less than 5 years. Despite extensive research efforts over the past decades, no currently available therapy has been shown to either reverse or even halt the progression of this disease. The "established" approach to treatment of IPF is based on the assumption that it is a chronic inflammatory disease, and most available antiinflammatory drugs, such as corticosteroids or cytotoxic agents, target numerous biological processes involving multiple genes. These drugs are not very beneficial for patients; the overall response rate may be in the range of 20 to 30% (1). However, it is worth mentioning that because prospective placebo-controlled clinical trials with immunosuppressive drugs have not been performed yet, it may not be justified to completely discredit their potential usefulness. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account and target only a few genes or even a single one (see Figure 1).


Figure 1
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  		Figure 1. The classical drugs used for treatment of interstitial pulmonary fibrosis targeted a very broad spectrum of biological processes involving multiple gene targets. More modern therapies, such as interferon or N-acetylcysteine, are less broad, but still target and affect numerous genes. Currently, several compounds targeting single genes are in development or in early clinical trials. Ultimately, it appears unlikely that targeting one single gene will result in a breakthrough in the treatment of interstitial pulmonary fibrosis, but that several key genes have to be influenced to make a real change. CTGF = connective tissue growth factor; PAI = plasminogen activator inhibitor; TGF-ß = transforming growth factor ß; TIMP = tissue inhibitor of metalloproteinase; TK = tyrosine kinase.

 
CURRENT TREATMENTS AND CLINICAL TRIALS IN IPF

Several properly designed clinical trials for IPF were published in the past few years. These trials investigated the effect of INF{gamma} and the antifibrotic compound pirfenidone (both in addition to a moderate dose of prednisone) and the antioxidant N-acetylcysteine (plus prednisone and azathioprine). Although none of these trials revealed a breakthrough in the management of IPF, the presented data suggest some beneficial effects, and are overall promising. These approaches are not, from a molecular perspective, less widespread than unspecific immunosuppression, but they still target a fairly large set of genes. Some of the ongoing and yet unpublished clinical trials in IPF aim to block single-gene targets believed to play major roles in disease progression. Some compounds currently investigated are a soluble receptor antagonizing the effects of tumor necrosis factor {alpha} (TNF-{alpha}; etanercept), monoclonal anti-antibodies against transforming growth factor ß (TGF-ß) and connective tissue growth factor (CTGF), and receptor antagonists for endothelin-1 (bosentan) and platelet-derived growth factor (PDGF)-B (imatinib mesylate; see http://www.coalitionforpf.org for an overview of clinical trials that are ongoing).

IDENTIFICATION OF KEY MEDIATORS FOR THE PROGRESSION OF PULMONARY FIBROSIS

To identify gene targets for IPF treatment, key events for the initiation and for the progression of the fibrotic process have to be characterized. This characterization of the mechanisms involved in the pathogenesis of IPF has largely come from the use of animal disease models in rodents. Pulmonary fibrosis can be induced by various means: (1) administration of toxic or inert compounds like bleomycin, silica, or asbestos; (2) irradiation; (3) use of transgenic knock-in or -out systems; (4) overexpression of a single factor at a time using a gene vector approach; or (5) combinations of the above reviewed in Reference 2.

These experimental models have helped to identify numerous factors as potential mediators of fibrosis, including TNF-{alpha} (3–5), TGF-ß (6–8), CTGF (9, 10), PDGF (6), endothelin (11, 12), interleukin (IL)-6 (6), granulocyte-macrophage colony–stimulating factor (GM-CSF) (13, 14), oncostatin M (15), IL-1ß (16), IL-10 (17), and IL-13 (17, 18). The fibrotic response described is largely variable. Some factors are related to severe inflammation (TNF-{alpha}, IL-1ß) or lack of inflammation (PDGF, TGF-ß1) or fibrotic phenotype; some cause reversible fibrosis (TNF-{alpha}, TGF-ß3, CTGF, IL-10, oncostatin M); others cause more progressive fibrosis (IL-1ß, TGF-ß1). Fibrosis can be accompanied by emphysematous changes (TNF-{alpha}, PDGF-B) but can also be absent (or not reported) (TGF-ß1, TGF-ß3, IL-10). Most data suggest, from among the different factors, a prominent role for the TGF-ß1 and PDGF pathways, which are discussed in more detail below.

PDGF

PDGF is a glycoprotein dimer composed of A or B chains, existing in the forms AA, BB, or AB. In the lung, it is secreted by platelets, macrophages, epithelial and endothelial cells, and by fibroblasts (19). Signal transduction proceeds through tyrosine kinases, a major pharmacologic target (20). PDGF isoforms are chemoattractive not only for fibroblasts but also for neutrophils and macrophages and they up-regulate fibronectin and procollagen gene expression and synthesis. PDGF can induce TGF-ß expression, suggesting that some of the long-term effects are partly mediated through this cytokine. On the other hand, PDGF and PDGF-receptor expression is stimulated by TGF-ß, IL-1ß, TNF-{alpha}, and basic fibroblast growth factor, indicating that parts of the profibrotic activities are due to PDGF-dependent pathways (21). In animals exposed to asbestos, both PDGF and its receptors are up-regulated in bronchial bifurcations with developing fibroproliferative lesions (22). Interference with PDGF activity, either through transgene overexpression of a truncated receptor or through inhibition of tyrosine kinase, resulted in amelioration of the fibrotic response in the bleomycin model and a model of bronchiolitis obliterans (21). In human fibrotic disorders of the lung, such as IPF, scleroderma, and bronchiolitis obliterans, PDGF genes were shown to be up-regulated in bronchoalveolar lavage cells or in affected tissues (21).

Imatinib is a tyrosine kinase inhibitor and inhibits the signaling through the receptor for PDGF. The compound (Gleevec) is indicated for treatment of chronic myeloid leukemia. Newer experimental studies demonstrated a beneficial effect of imatinib in pulmonary fibrosis (23, 24), through a non–Smad-dependent pathway, and the first clinical trial in the United States will expect results in summer 2006. It should be noted, however, that this drug has been reported to induce interstitial pneumonitis in some patients (see www.pneumotox.com), raising issues in using this drug in the treatment of IPF.

TGF-ß

There is substantial evidence for major implication of TGF-ß in the development of IPF (for reviews, see References 25 and 26). TGF-ß isoforms are multifunctional growth and differentiation factors affecting almost all cells. In the context of wound repair and fibrogenesis, TGF-ß induces myofibroblast differentiation, ECM synthesis, and inhibits matrix degradation. Data from both human IPF lungs and animal disease models support the pivotal role that TGF-ß might play for the development and progression of IPF. It has been shown that macrophages and lavage fluid from patients with IPF release large amounts of TGF-ß1 and that TGF-ß1 is present in fibroblastic foci in biopsies from patients with IPF (27). Gene expression studies in human tissue show marked up-regulation of TGF-ß responsive genes (28), and the best described animal disease model for pulmonary fibrosis, the bleomycin model, is largely driven by TGF-ß1 (29). Further, transgenic mice overexpressing TGF-ß1 and overexpression models of TGF-ß1 have shown that the presence of this cytokine alone is sufficient to induce a progressive fibrotic response independent of inflammation (7, 8).

Interference or blockage of the TGF-ß pathway in animal models can be achieved by different means (an overview of the complexity of TGF-ß structures and activation is given in Figure 2), and several approaches have successfully prevented the development of progressive PF. Abundant TGF-ß can be bound by decorin, an endogenous glycoprotein capable of inactivating TGF-ß by keeping it away from its receptor (30, 31). The activation of TGF-ß can be prevented by interference with the integrin {alpha}Vß6 (shown in {alpha}Vß6 null mice and with {alpha}Vß6 Ab; Reference 32). Signal transduction of TGF-ß after its binding to the receptor can be prevented by SD208, a tyrosine kinase inhibitor, or by blocking the intracellular Smad signaling pathway (Smad3 null mice are fibrosis resistant and overexpression of the inhibitory Smad7 is antifibrotic; References 33–35). However, it has to be mentioned that all successful experimental treatment approaches interfered with the initiation or early activation of the fibrotic response. This is in contrast to the clinical setting where the modulation of an ongoing progressive fibrotic process is warranted.


Figure 2
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  		Figure 2. Activation of transforming growth factor ß (TGF-ß). The activation of TGF-ß is critical to its activity (mRNA and protein content of TGF-ß does not correlate with activity). Interference with the individual components and subregions of the small and large latent TGF-ß complexes (described in the key) might interfere with its activation. Site-specific mechanisms might add to the complexity of the modulation of this activity. EFG = epidermal growth factor; LAP = latency associated protein; LTBP-1s = latent TGF-ß binding protein-1s; M6P = mannose 6-phosphate; TB module = TGF-ß binding protein-like domain.

 
Several pharmaceutical developments are underway targeting TGF-ß and its pathway. Among these are antibodies to TGFß interference with {alpha}Vß6 activation of TGF-ß tyrosine kinase inhibitors of the TGF-ß receptor and inhibition of intracellular signaling cascades. Some of these efforts are close to clinical trials, and the expectations in regard to these compounds are "cautiously positive."

CTGF

CTGF is a member of the cysteine rich-61 nephroblastoma family (36). The biological role of this factor is still unclear, but a growing body of evidence suggests that CTGF might be a downstream mediator of TGF-ß (37). In IPF tissue, high levels of CTGF have been found in proliferating type II alveolar cells and activated fibroblasts (38). Interestingly, CTGF seems to be affected by IFN-{gamma} treatment: in the first IFN-{gamma} trial involving a small number of patients, published in 1999, it was shown that CTGF mRNA was elevated in transbronchial biopsies from patients with IPF and that the gene expression levels decreased significantly after 1 yr of treatment (39). In rats, transient overexpression of CTGF induced a moderate but reversible fibrotic response (10). Further, concomitant overexpression of CTGF in bleomycin-treated fibrosis-resistant Balb/c mice, characterized by a lack of endogenous induction of the CTGF and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes (9, 40), was sufficient to cause lung fibrosis (40).

There are several possibilities to target CTGF; most important, a monoclonal antibody (FG-3019) directed toward CTGF has finished a phase I clinical trial, and the data are currently presented and discussed at international meetings. It is believed that CTGF might be a more specific target for antifibrotic therapies than TGF-ß, with the potential to provide significant clinical benefit without broad side effects.

TARGETING SPECIFIC MECHANISMS IN IPF

It would appear rational to believe that IPF is not a straightforward pathology and that targeting a single gene might not bring a breakthrough in the treatment unless the timing of therapy is perfectly suited. This problem can be bypassed not only by targeting several genes, but also by targeting more specific pathogenic mechanisms that are known or thought to be crucial components in the development of IPF. Some of these mechanisms are inflammation, myofibroblast origin and differentiation, and extracellular matrix metabolism.

WHERE WOULD INFLAMMATION-SPECIFIC GENE TARGETS FIT IN THE THERAPY FOR IPF?

It is recognized that repeated acute or chronic inflammation can cause a fibrogenic response in the lung and other organs. As a matter of fact, the most frequently used animal model for pulmonary fibrosis (bleomycin-induced lung fibrosis) is characterized by a severe inflammatory component and tissue destruction in the initial phase. However, it is subject of ongoing discussion if inflammation is required for the progression of fibrosis (41, 42). It may well be that the inflammatory component, if present, could be an epiphenomenon and less involved in the chronic phase of IPF. As an example, experimental overexpression of TGF-ß causes extensive fibrosis in mouse or rat lung without preceding major inflammation. In contrast, overexpression of IL-1ß in rat lung induces severe tissue destruction, inflammation, and subsequently progressive fibrosis (16). However, when IL-1ß is administered to Smad3 knockout mice, both tissue injury and inflammatory response are present, but the null mice do not progress to the fibrotic phenotype, indicating that the Smad pathway and not the inflammation is necessary for the development of pulmonary fibrosis, and that inflammation is linked to fibrosis through TGF-ß and Smad3 signaling (43). These data, together with the observation that no antiinflammatory drugs have been reported to reduce the progression of IPF, suggest that inflammation may not be a critical component of progressive IPF and targeting genes involved in the inflammatory response may not modify the progressive nature of IPF.

ORIGINS OF FIBROBLASTS AND MYOFIBROBLAST DIFFERENTIATION

Myofibroblasts are a major component of granulation and scar tissue. They are very efficient producers of ECM, including collagens and glycoprotein. The cellular origin of myofibroblasts and fibroblasts in scar tissue and fibroblastic foci in the lung is not clear. One concept is that they derive from local mesenchymal cells that are relatively quiescent but differentiate upon stimulation to highly active synthetic cells. Two other hypotheses are currently being investigated in several laboratories. One is the possibility that these cells originate from the nearby epithelium, a process called epithelial mesenchymal transition (EMT). Evidence for EMT has been provided in vivo in a kidney model of fibrosis (19), and it is estimated that up to 50% of mesenchymal cells in fibrotic kidneys develop from cells that underwent EMT (44). Some data suggest this to also occur in the lung, and in vitro studies using a human alveolar epithelial cell line have shown these cells could switch their phenotype and become fibroblasts after treatment with TGF-ß1, indicating the possible origin of fibroblastic foci typical of IPF (20, 22).

Fibroblasts might also originate from the bone marrow. Recently, it was reported that fibrocytes (circulating cells of hematopoietic origin) could be involved in the fibroproliferative process in the lung (45, 46). It is still unclear what importance these cellular pathways might have on the initiation and on the progression of IPF. However, a better understanding of the cell type implicated and their fate within the tissue (beneficial or detrimental) has to be obtained before targeting these processes for therapy.

ECM TURNOVER

One of the differences between physiologic wound repair after injury and fibrosis is the balance between deposition and degradation of ECM. Collagen may be best known as relatively inert biochemical substance, but it still has a daily turnover rate of approximately 10% (47). IPF is characterized not only by increased production and deposition of ECM but also by reduced degradation of collagen. The detailed knowledge of the mechanisms that contribute to degradation of extracellular collagen is therefore of immediate interest as they are potential targets for novel therapies. There are two main mechanisms involved in degradation of extracellular collagen: receptor-mediated phagocytosis and protease-mediated degradation. Comparative studies between fibrosis-sensitive and --resistant mouse strains have suggested that fibrosis develops in mice that up-regulate TIMP-1 following bleomycin injury or transient overexpression of TGF-ß (C57BL/6), but not in mice in which TIMP-1 gene is unchanged (Balb/c) (48). Another gene that may be targeted is plasminogen activator inhibitor-1 (PAI-1): mice with a null mutation in PAI-1 are relatively resistant to bleomycin fibrosis (49). Further indication about the importance of the fibrinolytic system in the bleomycin model and potentially IPF comes from experiments using transfer of the human urokinase-type plasminogen activator gene that reduced accumulation by 38% when gene transfer was done at Day 21 after bleomycin challenge (50). Aerosolized heparin and urokinase was also found to abrogate bleomycin-induced fibrosis in rabbits (51). Phase I clinical trials with inhaled heparin in patients with IPF are currently underway in Germany.

PROBLEMS ASSOCIATED WITH GENE TARGETED THERAPY

The identification of potential gene targets for treatment of a complex disease like IPF is a tedious task, but there are numerous pitfalls even if targets are identified and characterized. It is completely unclear when these treatment approaches should be initiated, and findings derived from experimental models are almost useless to answer this question. Data from human disease are not readily available and it is questionable if they will be in the foreseeable future as there are no established procedures for serial investigations of molecular markers in patients. Another problem is the route of drug delivery, and how to reach the diseased tissue compartments with the therapeutic compound. It is evident that tissue remodeling is a very heterogeneous process in terms of temporal and spatial distribution. A specific gene may be successfully targeted at one site and fibrosis might be prevented, but an adjacent site, also targeted by the same approach, might be damaged at the same time. In short, there is a theoretical risk that fibrosis is prevented by gene targeted therapies but this occurs at the price of matrix loss and emphysemalike lesions. Further, it has to be considered that the biological roles and networking of genes such as TGF-ß or PDGF are extremely complex. Interfering with this complexity could mean building up a long list of unwanted side effects.

CONCLUSIONS

Research efforts of the past 10 years have helped to bring some light into the complex pathogenesis of pulmonary fibrosis, leading to a paradigm shift and suggesting that IPF is not as much a chronic inflammatory disease but a disorder associated with impaired wound healing and injury repair. Several genes have been identified to be key players in the disease, and some of those are currently targeted for developing novel therapies. This is overall a very promising development that may ultimately result in an improvement of the clinical management of patients with IPF, but one should not forget that gene targeted therapy has numerous pitfalls that have to be addressed before it will become a real therapeutic advance.

FOOTNOTES

Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form February 21, 2006; accepted in final form February 27, 2006)

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