Digestive and Liver Disease 46 (2014) 293–294
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Editorial
The impact of translational research on gastroenterology Antonio Di Sabatino, Antonio Moschetta, Dario Conte, Claudio Tiribelli ∗ , Translational Committee of the Italian Society of Gastroenterology (SIGE)1 Italian Society of Gastroenterology (SIGE), Rome, Italy
a r t i c l e
i n f o
Article history: Received 11 November 2013 Accepted 20 December 2013 Available online 5 February 2014
In recent years, vast progress in basic science and technology has dramatically changed scientific perspectives by opening the new horizon of translational medicine. The term “translational” refers to the bench-to-bedside paradigm and addresses the process of applying ideas, insights and discoveries generated through basic science (chemistry, biology, genetics) to improve diagnosis, prevention and treatment of human diseases [1]. The bench-to-bedside process can be divided into several steps, from basic inquiry into pathophysiology to the identification of potentially targetable pathways, up to the development of new drugs. The final track resides in clinical testing of therapeutic agents and evaluation of their efficacy. Traditionally, these steps are performed by independent experts, starting from the basic scientist, through the chemistry expert/drug developer, ending with the clinical scientist. These professionals most of the time are physically separated, and very often use a different terminology with difficulties in cooperation and communication. The identification of a translational approach recognizes the strong need for a close interaction between individuals in science. Furthermore, sharing information among players also favours feedback from the clinician to the basic scientist, thus making research at least a two-way process, from bench-to-bedside and from bedside-to-bench [2]. In the last two decades, gastroenterology has become an area of dynamic translational research, with some targets already successfully translated into practice and policy, and some others still progressing into clinically effective drugs in a number of different conditions (Supplementary Figure S1). Epitome of how bidirectional translation has been fruitful in this field is the discovery of the central role of the potent pro-inflammatory cytokine tumour
∗ Corresponding author at: SIGE Office, Corso di Francia 197, 00191 Rome, Italy. Tel.: +39 06363 81188; fax: +39 06363 87434. E-mail address: [email protected] (C. Tiribelli). 1 See Appendix A for the Translational Committee of the Italian Society of Gastroenterology (SIGE) members.
necrosis factor (TNF)-␣ in chronic intestinal inflammation, which has ultimately led to the development of monoclonal antibodies specifically targeting this molecule in inflammatory bowel disease. These new biologic agents, first proved to be successful in ameliorating experimental colitis, turned out to be clinically effective in patients with Crohn’s disease, offering a further therapeutic chance to patients in whom conventional therapies had failed (bench-tobedside arm, Supplementary Figure S2) [3]. On the other hand, the therapeutic use of anti-TNF-␣ monoclonal antibodies has helped to clarify the immune mechanisms implicated in chronic gut inflammation such as: the crucial function of defective lamina propria T-cell apoptosis in sustaining tissue damage [4]; the wound repair function of subepithelial myofibroblasts in inducing mucosal healing [5]; the leading pathogenic action of TNF-␣ in ulcerative colitis, a disorder previously thought to be dominated by a Th2 response. In light of the failure of drugs exerting their therapeutic effect only by neutralizing soluble TNF-␣, i.e. pentoxifylline, and alongside the success of infliximab and adalimumab in Crohn’s disease, an important lesson can be obtained from the bedside-to-bench approach. To achieve a clinical benefit, cells, such as T cells and macrophages, instead of soluble cytokines, must be regarded as the true therapeutic targets, since they behave as the main players of tissue damage in inflammatory bowel disease, (bedside-to-bench arm, Supplementary Figure S2) [6]. This observation dramatically changed the fundamental strategy in developing therapeutic agents, now aimed at cells instead of cytokines, thus resulting in a more “pathogenetic” translational approach. Italy is playing a pivotal role in this emerging scenario by running a number of studies, as those by Dr. Monteleone’s group on transforming growth factor (TGF)- signalling and intestinal immune homeostasis. These studies are paradigmatic to highlight the concept of how the bench-to-bedside approach can be relevant in gastroenterology. TGF-1 is a powerful negative regulator of several mucosal inflammatory pathways in the gut, and neutralization of TGF-1 activity promotes and/or enhances pathologic responses. After showing high levels of Smad7 (an inhibitor of TGF-1
1590-8658/$36.00 © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dld.2013.12.015
294
A. Di Sabatino et al. / Digestive and Liver Disease 46 (2014) 293–294
signalling) in the inflamed Crohn’s disease mucosa, Monteleone et al. showed that targeted knockdown of Smad7 in mononuclear cells with a specific antisense oligonucleotide restores TGF-1 activity and attenuates experimental colitis in mice [7]. Hence, a Smad7 antisense oligonucleotide compound, termed GED0301, was developed and released in the terminal ileum and right colon where Crohn’s disease lesions are mostly localized. The exploratory phase 1 trial of GED0301 provided encouraging results in terms of clinical efficacy, safety and tolerability in active Crohn’s disease patients [8]. The phase II clinical trial currently underway will show the efficacy and long-term safety of GED0301 in Crohn’s disease patients. Regrettably, a major risk of these studies is to undertake a “long, long journey through the darkness and the shadow”. In fact, most basic science discoveries take more than a decade before being translated into a clinically relevant drug, and the high costs related to the development and approval of useful therapeutic compounds negatively affects pharmaceutical research. Moreover, while the large majority of government resources are directed to basic science discovery, drug development and clinical efficacy studies, only a relatively small amount of money is spent in evaluating how to best deliver therapy to patients. The rapid increase in basic knowledge not associated with the concomitant increase in delivering reliable care, resulted in what the American Institute of Medicine has termed “Quality Chasm” [9]. To overcome these roadblocks, the NIH has recently created a growing number of Clinical and Translational Science Awards programmes aimed at facilitating the transition from basic science discoveries to clinical studies, community practice, and health care decision making [10]. A discovery is precious when it can be translated into human physiology, and eventually pharmacology or novel diagnostics. However, it has become very common in basic gastroenterology to chase research projects whose actual link to human disease is at least not clearly evident. The large amount of scientific information of the last fifty years generated areas of ultraspecialization in multiple restricted areas of biology, which now act as independent disciplines, sometimes moving away from the original pursuit of improving knowledge of human health. Examples are the amount of data derived from experimental models, which may have little value when translating to humans. Many studies showed that the inhibition of cytokines, such as interferon (IFN)-␥ and interleukin (IL)-17, is a highly effective therapy in some experimental colitis. Unfortunately, the positive effects did not always translate into clinical effectiveness in humans; both fontolizumab (anti-IFN␥ monoclonal antibody) and secukinumab (anti-IL17A monoclonal antibody) failed in the treatment of patients with Crohn’s disease [11,12]. Although animal models represent an invaluable tool to identify biological mechanisms and offer the possibility to test hypotheses that can provide a solid background to develop new drugs, it must be recognized that the direct translation of data obtained in these models in humans has been sometimes unsuccessful. These observations should lead researchers involved in basic science to tighten the interaction with clinicians in order to gain access to clinical information and human material and vice versa, to make clinicians aware of the effective range of preclinical data thus increasing the rate of success in the translation of results from the bench to the bedside. In conclusion, in the last few years translational research has made incredible progress in gastroenterology thanks to the
development of novel technologies, new infrastructures and specific studies aimed at drug-development and testing. However, the transition is not complete and roadblocks still exist on the way to scientific progress. Translational gastroenterology must be reprioritized and encouraged in a way that increases the speed at which promising drugs and technologies move through the pipeline into clinical application. Caution is strongly recommended until results of basic studies will be confirmed in the much more complex human settings. Collectively this means to bring close together basic and clinical scientists in a joint endeavour to make the bench-to-bed round trip useful and fruitful. This is one of the targets of the Translational Committee of the Italian Society of Gastroenterology. Conflict of interest statement G.M. filed a patent entitled “Antisense oligonucleotides (odn) against smad7 and uses thereof in medical field”. All other authors declare no competing financial interests. Appendix A. Translational Committee of the Italian Society of Gastroenterology (SIGE): Flavio Andrea Caprioli, Luca Fabris, Massimo C. Fantini, Luca Frulloni, Giovanni Monteleone, Marco Romano, Giovanni Sarnelli, Gianluca Svegliati Baroni Appendix B. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2013.12.015. References [1] Zerhouni EA. Translational and clinical science-time for a new vision. N Engl J Med 2005;353:1621–30. [2] Woolf SH. The meaning of translational research and why it matters. J Am Med Assoc 2008;299:211–3. [3] Caprioli F, Caruso R, Sarra M, et al. Disruption of inflammatory signals by cytokine-targeted therapies for inflammatory bowel diseases. Br J Pharmacol 2012;165:820–8. [4] Ten Hove T, van Montfrans C, Peppelenbosch MP, et al. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut 2002;50:206–11. [5] Di Sabatino A, Pender SLF, Jackson CL, et al. Functional modulation of Crohn’s disease myofibroblasts by anti-TNF antibodies. Gastroenterology 2007;133:137–49. [6] MacDonald TT. Inside the microbial and immune labyrinth: totally gutted. Nat Med 2010;16:1194–200. [7] Monteleone G, Kumberova A, Croft NM, et al. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest 2001;108:601–9. [8] Monteleone G, Fantini MC, Onali S, et al. Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn’s disease. Mol Ther 2012;20:870–6. [9] Crandall W. T3 translational science in gastroenterology: getting to best outcomes. Clin Gastroenterol Hepatol 2013;11:1559–60, pii:S1542-3565(13)01510-3. [10] Kaitin KI. Translational research and the evolving landscape for biomedical innovation. J Investig Med 2012;60:995–8. [11] Reinisch W, de Villiers W, Bene L, et al. Fontolizumab in moderate to severe Crohn’s disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 2010;16:233–42. [12] Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 2012;61:1693–700.
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Editorial
The impact of translational research on gastroenterology Antonio Di Sabatino, Antonio Moschetta, Dario Conte, Claudio Tiribelli ∗ , Translational Committee of the Italian Society of Gastroenterology (SIGE)1 Italian Society of Gastroenterology (SIGE), Rome, Italy
a r t i c l e
i n f o
Article history: Received 11 November 2013 Accepted 20 December 2013 Available online 5 February 2014
In recent years, vast progress in basic science and technology has dramatically changed scientific perspectives by opening the new horizon of translational medicine. The term “translational” refers to the bench-to-bedside paradigm and addresses the process of applying ideas, insights and discoveries generated through basic science (chemistry, biology, genetics) to improve diagnosis, prevention and treatment of human diseases [1]. The bench-to-bedside process can be divided into several steps, from basic inquiry into pathophysiology to the identification of potentially targetable pathways, up to the development of new drugs. The final track resides in clinical testing of therapeutic agents and evaluation of their efficacy. Traditionally, these steps are performed by independent experts, starting from the basic scientist, through the chemistry expert/drug developer, ending with the clinical scientist. These professionals most of the time are physically separated, and very often use a different terminology with difficulties in cooperation and communication. The identification of a translational approach recognizes the strong need for a close interaction between individuals in science. Furthermore, sharing information among players also favours feedback from the clinician to the basic scientist, thus making research at least a two-way process, from bench-to-bedside and from bedside-to-bench [2]. In the last two decades, gastroenterology has become an area of dynamic translational research, with some targets already successfully translated into practice and policy, and some others still progressing into clinically effective drugs in a number of different conditions (Supplementary Figure S1). Epitome of how bidirectional translation has been fruitful in this field is the discovery of the central role of the potent pro-inflammatory cytokine tumour
∗ Corresponding author at: SIGE Office, Corso di Francia 197, 00191 Rome, Italy. Tel.: +39 06363 81188; fax: +39 06363 87434. E-mail address: [email protected] (C. Tiribelli). 1 See Appendix A for the Translational Committee of the Italian Society of Gastroenterology (SIGE) members.
necrosis factor (TNF)-␣ in chronic intestinal inflammation, which has ultimately led to the development of monoclonal antibodies specifically targeting this molecule in inflammatory bowel disease. These new biologic agents, first proved to be successful in ameliorating experimental colitis, turned out to be clinically effective in patients with Crohn’s disease, offering a further therapeutic chance to patients in whom conventional therapies had failed (bench-tobedside arm, Supplementary Figure S2) [3]. On the other hand, the therapeutic use of anti-TNF-␣ monoclonal antibodies has helped to clarify the immune mechanisms implicated in chronic gut inflammation such as: the crucial function of defective lamina propria T-cell apoptosis in sustaining tissue damage [4]; the wound repair function of subepithelial myofibroblasts in inducing mucosal healing [5]; the leading pathogenic action of TNF-␣ in ulcerative colitis, a disorder previously thought to be dominated by a Th2 response. In light of the failure of drugs exerting their therapeutic effect only by neutralizing soluble TNF-␣, i.e. pentoxifylline, and alongside the success of infliximab and adalimumab in Crohn’s disease, an important lesson can be obtained from the bedside-to-bench approach. To achieve a clinical benefit, cells, such as T cells and macrophages, instead of soluble cytokines, must be regarded as the true therapeutic targets, since they behave as the main players of tissue damage in inflammatory bowel disease, (bedside-to-bench arm, Supplementary Figure S2) [6]. This observation dramatically changed the fundamental strategy in developing therapeutic agents, now aimed at cells instead of cytokines, thus resulting in a more “pathogenetic” translational approach. Italy is playing a pivotal role in this emerging scenario by running a number of studies, as those by Dr. Monteleone’s group on transforming growth factor (TGF)- signalling and intestinal immune homeostasis. These studies are paradigmatic to highlight the concept of how the bench-to-bedside approach can be relevant in gastroenterology. TGF-1 is a powerful negative regulator of several mucosal inflammatory pathways in the gut, and neutralization of TGF-1 activity promotes and/or enhances pathologic responses. After showing high levels of Smad7 (an inhibitor of TGF-1
1590-8658/$36.00 © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dld.2013.12.015
294
A. Di Sabatino et al. / Digestive and Liver Disease 46 (2014) 293–294
signalling) in the inflamed Crohn’s disease mucosa, Monteleone et al. showed that targeted knockdown of Smad7 in mononuclear cells with a specific antisense oligonucleotide restores TGF-1 activity and attenuates experimental colitis in mice [7]. Hence, a Smad7 antisense oligonucleotide compound, termed GED0301, was developed and released in the terminal ileum and right colon where Crohn’s disease lesions are mostly localized. The exploratory phase 1 trial of GED0301 provided encouraging results in terms of clinical efficacy, safety and tolerability in active Crohn’s disease patients [8]. The phase II clinical trial currently underway will show the efficacy and long-term safety of GED0301 in Crohn’s disease patients. Regrettably, a major risk of these studies is to undertake a “long, long journey through the darkness and the shadow”. In fact, most basic science discoveries take more than a decade before being translated into a clinically relevant drug, and the high costs related to the development and approval of useful therapeutic compounds negatively affects pharmaceutical research. Moreover, while the large majority of government resources are directed to basic science discovery, drug development and clinical efficacy studies, only a relatively small amount of money is spent in evaluating how to best deliver therapy to patients. The rapid increase in basic knowledge not associated with the concomitant increase in delivering reliable care, resulted in what the American Institute of Medicine has termed “Quality Chasm” [9]. To overcome these roadblocks, the NIH has recently created a growing number of Clinical and Translational Science Awards programmes aimed at facilitating the transition from basic science discoveries to clinical studies, community practice, and health care decision making [10]. A discovery is precious when it can be translated into human physiology, and eventually pharmacology or novel diagnostics. However, it has become very common in basic gastroenterology to chase research projects whose actual link to human disease is at least not clearly evident. The large amount of scientific information of the last fifty years generated areas of ultraspecialization in multiple restricted areas of biology, which now act as independent disciplines, sometimes moving away from the original pursuit of improving knowledge of human health. Examples are the amount of data derived from experimental models, which may have little value when translating to humans. Many studies showed that the inhibition of cytokines, such as interferon (IFN)-␥ and interleukin (IL)-17, is a highly effective therapy in some experimental colitis. Unfortunately, the positive effects did not always translate into clinical effectiveness in humans; both fontolizumab (anti-IFN␥ monoclonal antibody) and secukinumab (anti-IL17A monoclonal antibody) failed in the treatment of patients with Crohn’s disease [11,12]. Although animal models represent an invaluable tool to identify biological mechanisms and offer the possibility to test hypotheses that can provide a solid background to develop new drugs, it must be recognized that the direct translation of data obtained in these models in humans has been sometimes unsuccessful. These observations should lead researchers involved in basic science to tighten the interaction with clinicians in order to gain access to clinical information and human material and vice versa, to make clinicians aware of the effective range of preclinical data thus increasing the rate of success in the translation of results from the bench to the bedside. In conclusion, in the last few years translational research has made incredible progress in gastroenterology thanks to the
development of novel technologies, new infrastructures and specific studies aimed at drug-development and testing. However, the transition is not complete and roadblocks still exist on the way to scientific progress. Translational gastroenterology must be reprioritized and encouraged in a way that increases the speed at which promising drugs and technologies move through the pipeline into clinical application. Caution is strongly recommended until results of basic studies will be confirmed in the much more complex human settings. Collectively this means to bring close together basic and clinical scientists in a joint endeavour to make the bench-to-bed round trip useful and fruitful. This is one of the targets of the Translational Committee of the Italian Society of Gastroenterology. Conflict of interest statement G.M. filed a patent entitled “Antisense oligonucleotides (odn) against smad7 and uses thereof in medical field”. All other authors declare no competing financial interests. Appendix A. Translational Committee of the Italian Society of Gastroenterology (SIGE): Flavio Andrea Caprioli, Luca Fabris, Massimo C. Fantini, Luca Frulloni, Giovanni Monteleone, Marco Romano, Giovanni Sarnelli, Gianluca Svegliati Baroni Appendix B. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2013.12.015. References [1] Zerhouni EA. Translational and clinical science-time for a new vision. N Engl J Med 2005;353:1621–30. [2] Woolf SH. The meaning of translational research and why it matters. J Am Med Assoc 2008;299:211–3. [3] Caprioli F, Caruso R, Sarra M, et al. Disruption of inflammatory signals by cytokine-targeted therapies for inflammatory bowel diseases. Br J Pharmacol 2012;165:820–8. [4] Ten Hove T, van Montfrans C, Peppelenbosch MP, et al. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut 2002;50:206–11. [5] Di Sabatino A, Pender SLF, Jackson CL, et al. Functional modulation of Crohn’s disease myofibroblasts by anti-TNF antibodies. Gastroenterology 2007;133:137–49. [6] MacDonald TT. Inside the microbial and immune labyrinth: totally gutted. Nat Med 2010;16:1194–200. [7] Monteleone G, Kumberova A, Croft NM, et al. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest 2001;108:601–9. [8] Monteleone G, Fantini MC, Onali S, et al. Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn’s disease. Mol Ther 2012;20:870–6. [9] Crandall W. T3 translational science in gastroenterology: getting to best outcomes. Clin Gastroenterol Hepatol 2013;11:1559–60, pii:S1542-3565(13)01510-3. [10] Kaitin KI. Translational research and the evolving landscape for biomedical innovation. J Investig Med 2012;60:995–8. [11] Reinisch W, de Villiers W, Bene L, et al. Fontolizumab in moderate to severe Crohn’s disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 2010;16:233–42. [12] Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 2012;61:1693–700.
