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Astrocytes and glaucomatous neurodegeneration
Experimental Eye Research xxx (2017) 1e4
Contents lists available at ScienceDirect
Experimental Eye Research journal homepage: www.elsevier.com/locate/yexer
Editorial
Astrocytes and glaucomatous neurodegeneration
1. The Lasker/IRRF Initiative for Innovation in Vision Science Glaucoma is the leading cause of irreversible blindness throughout the world (Kingman, 2004; Resnikoff et al., 2004). 60.5 million people were affected worldwide in 2010 (Quigley and Broman, 2006), a number that is projected to increase to 111.8 million in 2040 (Tham et al., 2014). Glaucoma is an optic neuropathy with typical defects in optic disc structure and visual function leading to a characteristic pattern of visual field loss (Foster et al., 2002; Quigley, 2011). Multiple prospective randomized multi-center studies have identified intraocular pressure (IOP) as a critical risk factor for the pathogenesis of glaucoma (Collaborative Normal-Tension Glaucoma Study Group, 1998a, b; Kass et al., 2002; Leske et al., 2003; The AGIS Investigators, 2000). Consequently, glaucoma treatment aims at medically or surgically reducing IOP, which is currently the only proven method to treat glaucoma (Boland et al., 2013). Still, while therapy reduces the rate of progressive vision loss over the lifetime of many patients, the loss of visual field continues in a certain percentage (Quigley, 2011). Moreover, the available surgical techniques that are required in advanced forms of glaucoma to lower IOP may lead to visionthreatening complications. Overall, the current situation makes it mandatory to further study the mechanisms that are behind optic nerve axonal degeneration in region of the ONH with the ultimate goal to identify novel ways to treat glaucoma. There is considerable evidence pointing to the optic nerve head (ONH) as the critical site in the initiation of glaucomatous damage. Support for this assumption comes from experimental studies in monkey (Quigley et al., 1981) and mouse (Howell et al., 2007) models of glaucoma. In addition, there are clinical entities that involve the ONH and mimic the phenotype of glaucoma, such as anterior ischemic optic neuropathy (AION), drusen at the optic nerve head, chronic papilledema, juxtapapillary choroiditis and optic nerve head splinter hemorrhages (Tamm et al., 2013). Despite
1 About the Albert and Mary Lasker Foundation: Founded in 1942, the Albert and Mary Lasker Foundation envisions a healthier world through sustained support for basic and clinical medical research. The Foundation works to accomplish its mission through education and advocacy and, most notably, through a prestigious annual awards program. Lasker Award winners are selected by their peers, who, like themselves, include the world's most accomplished and well-respected medical research scientists, and thus the award represents a special honor. The Foundation's education and advocacy missions focus on engaging the public and policymakers on the importance of robust medical research programs and the funding to make them possible. The Lasker Foundation is also dedicated to supporting and inspiring the next generation of research scientists. For more information about the Lasker Foundation and its programs, visit http://www.laskerfoundation.org.
considerable research efforts over the past decades, our knowledge of the cellular and molecular mechanisms that cause glaucomatous optic nerve axonal degeneration at the ONH remains largely incomplete. The Lasker/IRRF Initiative for Innovation in Vision Science is a ten-year collaboration, launched in July 2008, between the Albert and Mary Lasker Foundation (Lasker)1 and the International Retinal Research Foundation (IRRF).2 The Initiative was designed to identify knowledge gaps in retinal and ophthalmic research and propose innovative strategies to accelerate the discovery of sight-saving treatments and prevention of retinal degenerative diseases using novel scientific, engineering and technological approaches. The Initiative's first report, Astrocytes and Glaucomatous Neurodegeneration, was published in November 2010 (a copy of the report is available at http://www.irrfonline.org/laskerirrf.html or http:// www.laskerfoundation.org/programs/irrf.htm). Since then, there is general agreement that significant scientific progress has occurred in the field. For example, it now is commonly accepted that astrocytes are a critical element of glaucoma pathophysiology, and advances in understanding the optic nerve head using new animal models have moved the field considerably. In 2014, the Initiative's Joint Advisory Board agreed that it would be valuable, both to the Initiative and to vision research, to evaluate where the field is now, whether and how the 2010 report stimulated innovative lines of research, what scientific hurdles have been overcome and what problems now confront the field. A Steering Committee was established to define goals and key issues for exploration by invited participants, which included many scientists from the first Initiative as well as some additional scientists. In March 2015, following an invitation by the Lasker/IRRF Initiative for Innovation in Vision Science, more than 40 scientists from all over the world met at the Howard Hughes Medical Institute Janelia Research Campus in Ashburn, Virginia (Fig. 1). They discussed the current status in the field and identified questions, topics and experiments that should be addressed within the next five years. The meeting format strongly emphasized discussion and 2 About the International Retinal Research Foundation: The International Retinal Research Foundation (IRRF) upholds a commitment to accelerate and sustain targeted research efforts into the diseases of the human eye, especially those affecting the retina and macula, to discover the causes, preventions, and cures of retinal and macular degenerative diseases and diabetic retinopathy. The IRRF accomplishes its mission by providing financial support for vision research directly, as well as through training fellowships, public awareness programs, and the promotion of the exchange of research findings. For more information about the IRRF, please visit www.irrfonline.org.
http://dx.doi.org/10.1016/j.exer.2017.02.013 0014-4835/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: Tamm, E.R., Dowling, J.E.Astrocytes and glaucomatous neurodegeneration, Experimental Eye Research (2017), http://dx.doi.org/10.1016/j.exer.2017.02.013
2
Editorial / Experimental Eye Research xxx (2017) 1e4
Fig. 1. Impressions from the March 2015 Lasker/IRRF Initiative for Innovation in Vision Science meeting “Astrocytes and Glaucomatous Neurodegeneration” at the Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia.
concentrated on questions within five general areas of research: 1. 2. 3. 4. 5.
Glial Cells, Ganglion Cells, and the Optic Nerve Head Astrocytes and Biomechanics Inflammation and Glaucomatous Neurodegeneration Optic Nerve Regeneration and Neurorepair Neuroprotection and What Is Needed Clinically
All areas were covered in presentations and keynote lectures followed by specific targeted sessions for which the steering committee had identified specific points for discussion. The ideas that came up at the targeted session were presented to all participants at the meeting and discussed. Finally, co-chairs and scribes summarized the results of each targeted session in five review articles that are now published in this special issue of Experimental Eye Research. The first article by Tamm and Ethier (2017, in press) reviews the possible molecular and cellular mechanisms that are behind axonal damage in glaucoma. An increase in strain of the peripapillary sclera that surrounds the ONH is identified as a possible initiating event that may trigger astrocyte reactivity in the ONH, putatively via transforming growth factor-b signaling. Reactive astrocytes in the ONH are expected to change homeostasis in the ONH microenvironment causing axonal degeneration. In a second article, by Stowell et al. (2017, in press), the current concepts on the biomechanical changes in the ONH and the exciting data that have been generated on this issue in the last few years are discussed. It is expected that more knowledge on the biomechanical forces that act on this tissue in the normal eye and in those with glaucoma is critical to understand the mechanisms that lead to structural changes at the ONH. An entirely novel concept to explain axonal damage in glaucoma is presented in a third article by Williams et al. (2017, in press). Here the available data that point to a neuroinflammatory origin of optic nerve damage in glaucoma are discussed and strategies are introduced that will help to explore this concept in more detail. Calkins et al. (2017, in press) provide a fourth article that highlights the available options to develop regenerative therapies for optic nerve axons that were damaged in glaucoma. They discuss the problems that need to be solved, such as preventing astrocyte reactivity and neuroinflammation at the ONH through which regenerating axons need to pass, but also the challenge to ensure that the connections with appropriate targets are formed in the brain. Finally, in a fifth article by Levin et al. (2017, in press), the requirements are discussed that are needed to initiate a neuroprotective therapy that will work not only in animal models with glaucoma,
but one that also has the potential to be translated into clinical practice. 2. Concluding Remarks As noted in the Concluding Remarks at the end of the Initiative's first report, glaucoma remains an intractable condition. But progress is being made, as detailed in this report; new ideas and approaches are being pursued and new facts and concepts elucidated. The energy, enthusiasm and imagination shown by the participants at the Janelia Research Campus meeting in March, 2015 bodes well for the future and for a breakthrough in dealing with this blinding disease. It is useful to note that glaucoma remains second on the list of blinding eye diseases in the United States, surpassed only by severe cataracts. Whereas some light perception remains in those suffering from severe cataracts, total blindness occurs in those with late-stage glaucoma. The need for a way to prevent glaucoma is very great, and the Lasker/IRRF Initiative hopes that the two meetings it has sponsored on glaucoma have helped get us closer to the day when this dreaded disease can be prevented. Steering committee John E. Dowling, Harvard University, Cambridge, MA, USA (Chair). Claude F. Burgoyne, Devers Eye Institute, Portland, OR, USA. David J. Calkins, Vanderbilt University, Nashville, TN, USA. Larry A. Donoso, Wills Eye Hospital & Jefferson Medical College, Philadelphia, PA, USA. Alan M. Laties, University of Pennsylvania, Philadelphia, PA, USA. al, QC, Canada. Leonard A. Levin, McGill University, Montre €t Erlangen-Nürnberg, Erlangen, Elke Lütjen-Drecoll, Universita Germany. Richard H. Masland, Harvard Medical School, Boston, MA, USA. Participants Larry Benowitz, Harvard Medical School, Boston, MA, USA. Alejandra Bosco, The University of Utah, Salt Lake City, UT, USA. Tailoi Chan-Ling, University of Sydney, Sydney, Australia. Francesca Cordeiro, University College, London, UK. Jonathan Crowston, University of Melbourne, Melbourne, Australia. John Danias, SUNY Downstate Medical Center, Brooklyn, NY,
Please cite this article in press as: Tamm, E.R., Dowling, J.E.Astrocytes and glaucomatous neurodegeneration, Experimental Eye Research (2017), http://dx.doi.org/10.1016/j.exer.2017.02.013
Editorial / Experimental Eye Research xxx (2017) 1e4
USA. al, QC, Canada. Adriana Di Polo, University of Montreal, Montre J. Crawford Downs, University of Alabama, Birmingham, AL, USA. Mark H. Ellisman, University of California San Diego, La Jolla, CA, USA. C. Ross Ethier, Georgia Institute of Technology and Emory University Medical School, Atlanta, GA, USA. Steven Fisher, University of California Santa Barbara, Santa Barbara, CA, USA. Brad Fortune, Devers Eye Institute, Portland, OR, USA. Marcus Fruttiger, University College, London, UK. Gareth Howell, The Jackson Laboratory, Bar Harbor, ME, USA. Andrew Huberman, Stanford University, Palo Alto, CA, USA. Tatjana C. Jakobs, Harvard Medical School, Boston, MA, USA. Elaine Johnson, Oregon Health and Science University, Portland, OR, USA. Markus Kuehn, University of Iowa, Iowa City, IA, USA. Geoffrey Lewis, University of California, Santa Barbara, Santa Barbara, CA, USA. Y. Joyce Liao, Stanford University, Palo Alto, CA, USA. Richard T. Libby, University of Rochester, Rochester, NY, USA. Richard Lu, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Nicholas Marsh-Armstrong, Johns Hopkins University, Baltimore, MD, USA. Claire H. Mitchell, University of Pennsylvania, Philadelphia, PA, USA. John Morrison, Oregon Health and Science University, Portland, OR, USA. Robert W. Nickells, University of Wisconsin-Madison, Madison, WI, USA. € teborg University, Milos Pekny, Sahlgrenska Academy at Go € teborg, Sweden. Go Hemali Phatnani, Columbia University, New York, NY, USA. Serge Przedborski Columbia University, New York, NY, USA. Harry A. Quigley, Johns Hopkins University, Baltimore, MD, USA. Martin Raff, University College, London, UK. Rebecca Sappington, Vanderbilt University, Nashville, TN, USA. Paul A. Sieving, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. Sansar Sharma, New York Medical College, Valhalla, NY, USA. Ian Sigal, University of Pittsburgh, Pittsburgh, PA, USA. Michael V. Sofroniew, University of California Los Angeles, Los Angeles, CA, USA. Alfred Sommer, Johns Hopkins University, Baltimore, MD, USA. Ernst R. Tamm, University of Regensburg, Regensburg, Germany. Ian Trounce, University of Melbourne, Melbourne, Australia. Lin Wang, Devers Eye Institute, Portland, OR, USA. Janey Wiggs, Harvard Medical School, Boston, MA, USA. Samuel Wu, Baylor College of Medicine, Houston, TX, USA. Don Zack, Johns Hopkins University, Baltimore, MD, USA. Scribes Melissa Cooper Vanderbilt University, Nashville, TN, USA. Megan Crowe, University of Wisconsin-Madison, Madison, WI, USA. Cheri Stowell, Devers Eye Institute, Portland, OR, USA. Peter Williams, The Jackson Laboratory, Bar Harbor, ME, USA. Collaborating executives Sandra Blackwood, Executive Director, International Retinal Research Foundation. Birmingham, AL, USA.
3
Claire Pomeroy, President, Albert and Mary Lasker Foundation, New York, NY, USA. Acknowledgments The Initiative thanks the Boards of Directors of the Albert and Mary Lasker Foundation and the International Retinal Research Foundation for their support; the Initiative's Joint Advisory Board and Steering Committee, for their counsel; the session co-chairs who guided the development of the key issues discussed in this report and the scribes who recorded the discussions and drafted chapter texts; and all participants, for their energy, expertise, and lively discourse. Special thanks go to Karen M. Wright, Program Administrator for her diligent and essential administrative direction; to Kate Guthrie, Program Manager, for her logistical support; and to Sandra Blackwood, Executive Director of the IRRF, and Claire Pomeroy, President of Lasker, for their constancy and contributions to this endeavor. The Initiative gratefully acknowledges the Howard Hughes Medical Institute for its very generous in-kind contribution by making available the facilities at its Janelia Research Campus in Ashburn, Virginia, for the March 2015 meeting. Last but not least, we thank the Editor-in-Chief, Joe Hollyfield, and the publisher for giving us the opportunity to publish this Special Issue in Experimental Eye Research. References Boland, M.V., Ervin, A.M., Friedman, D.S., Jampel, H.D., Hawkins, B.S., Vollenweider, D., Chelladurai, Y., Ward, D., Suarez-Cuervo, C., Robinson, K.A., 2013. Comparative effectiveness of treatments for open-angle glaucoma: a systematic review for the U.S. Preventive Services Task Force. Ann. Intern Med. 158, 271e279. Calkins, D.J., Pekny, M., Cooper, M.L., Benowitz, L.I., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. The challenge of regenerative therapies for the optic nerve in glaucoma. Exp. Eye Res. http://dx.doi.org/10.1016/j.exer.2017.01.007 (in press). Collaborative Normal-Tension Glaucoma Study Group, 1998a. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am. J. Ophthalmol. 126, 487e497. Collaborative Normal-Tension Glaucoma Study Group, 1998b. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group Am. J. Ophthalmol. 126, 498e505. Foster, P.J., Buhrmann, R., Quigley, H.A., Johnson, G.J., 2002. The definition and classification of glaucoma in prevalence surveys. Br. J. Ophthalmol. 86, 238e242. Howell, G.R., Libby, R.T., Jakobs, T.C., Smith, R.S., Phalan, F.C., Barter, J.W., Barbay, J.M., Marchant, J.K., Mahesh, N., Porciatti, V., Whitmore, A.V., Masland, R.H., John, S.W., 2007. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J. Cell Biol. 179, 1523e1537. Kass, M.A., Heuer, D.K., Higginbotham, E.J., Johnson, C.A., Keltner, J.L., Miller, J.P., Parrish 2nd, R.K., Wilson, M.R., Gordon, M.O., 2002. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch. Ophthalmol. 120, 701e713 discussion 829e730. Kingman, S., 2004. Glaucoma is second leading cause of blindness globally. Bull. World Health Organ 82, 887e888. Leske, M.C., Heijl, A., Hussein, M., Bengtsson, B., Hyman, L., Komaroff, E., 2003. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch. Ophthalmol. 121, 48e56. Levin, L.A., Quigley, H.A., Crowe, M.E., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. Neuroprotection for glaucoma: requirements for clinical translation. Exp. Eye Res. http://dx.doi.org/ 10.1016/j.exer.2016.12.005 (in press). Quigley, H.A., 2011. Glaucoma. Lancet 377, 1367e1377. Quigley, H.A., Addicks, E.M., Green, W.R., Maumenee, A.E., 1981. Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch. Ophthalmol. 99, 635e649. Quigley, H.A., Broman, A.T., 2006. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 90, 262e267. Resnikoff, S., Pascolini, D., Etya'ale, D., Kocur, I., Pararajasegaram, R., Pokharel, G.P., Mariotti, S.P., 2004. Global data on visual impairment in the year 2002. Bull. World Health Organ 82, 844e851. Stowell, C., Burgoyne, C., Tamm, E.R., Ethier, C.R., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. Biomechanical aspects of axonal damage in glaucoma: a brief review. Exp. Eye Res. http://
Please cite this article in press as: Tamm, E.R., Dowling, J.E.Astrocytes and glaucomatous neurodegeneration, Experimental Eye Research (2017), http://dx.doi.org/10.1016/j.exer.2017.02.013
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Editorial / Experimental Eye Research xxx (2017) 1e4
dx.doi.org/10.1016/j.exer.2017.02.005 (in press). Tamm, E.R., Ethier, C.R., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. Biological aspects of axonal damage in glaucoma: a brief review. Exp. Eye Res. http://dx.doi.org/10.1016/ j.exer.2017.02.006 (in press). Tamm, E.R., Schmetterer, L., Grehn, F., 2013. Status and perspectives of neuroprotective therapies in glaucoma: the European glaucoma society white paper. Cell Tissue Res. 353, 347e354. Tham, Y.C., Li, X., Wong, T.Y., Quigley, H.A., Aung, T., Cheng, C.Y., 2014. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 121, 2081e2090. The AGIS Investigators, 2000. The advanced glaucoma intervention study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am. J. Ophthalmol. 130, 429e440. Williams, P.A., Marsh-Armstrong, N., Howell, G.R., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. Neuroinflammation in glaucoma: a new opportunity. Exp. Eye Res. http://dx.doi.org/ 10.1016/j.exer.2017.02.014 (in press).
Ernst R. Tamm, M.D., Professor and Chairman* Institute of Human Anatomy & Embryology, University of Regensburg, €tsstr. 31, D-93053 Regensburg, Germany Universita John E. Dowling, PhD., Gordon and Llura Gund Research Professor of Neurosciences NWL-347.2 Harvard University, 52 Oxford Street, Cambridge, MA 02138, United States E-mail address: [email protected]. * Corresponding author. E-mail address: [email protected] (E.R. Tamm).
Available online xxx
Please cite this article in press as: Tamm, E.R., Dowling, J.E.Astrocytes and glaucomatous neurodegeneration, Experimental Eye Research (2017), http://dx.doi.org/10.1016/j.exer.2017.02.013
Contents lists available at ScienceDirect
Experimental Eye Research journal homepage: www.elsevier.com/locate/yexer
Editorial
Astrocytes and glaucomatous neurodegeneration
1. The Lasker/IRRF Initiative for Innovation in Vision Science Glaucoma is the leading cause of irreversible blindness throughout the world (Kingman, 2004; Resnikoff et al., 2004). 60.5 million people were affected worldwide in 2010 (Quigley and Broman, 2006), a number that is projected to increase to 111.8 million in 2040 (Tham et al., 2014). Glaucoma is an optic neuropathy with typical defects in optic disc structure and visual function leading to a characteristic pattern of visual field loss (Foster et al., 2002; Quigley, 2011). Multiple prospective randomized multi-center studies have identified intraocular pressure (IOP) as a critical risk factor for the pathogenesis of glaucoma (Collaborative Normal-Tension Glaucoma Study Group, 1998a, b; Kass et al., 2002; Leske et al., 2003; The AGIS Investigators, 2000). Consequently, glaucoma treatment aims at medically or surgically reducing IOP, which is currently the only proven method to treat glaucoma (Boland et al., 2013). Still, while therapy reduces the rate of progressive vision loss over the lifetime of many patients, the loss of visual field continues in a certain percentage (Quigley, 2011). Moreover, the available surgical techniques that are required in advanced forms of glaucoma to lower IOP may lead to visionthreatening complications. Overall, the current situation makes it mandatory to further study the mechanisms that are behind optic nerve axonal degeneration in region of the ONH with the ultimate goal to identify novel ways to treat glaucoma. There is considerable evidence pointing to the optic nerve head (ONH) as the critical site in the initiation of glaucomatous damage. Support for this assumption comes from experimental studies in monkey (Quigley et al., 1981) and mouse (Howell et al., 2007) models of glaucoma. In addition, there are clinical entities that involve the ONH and mimic the phenotype of glaucoma, such as anterior ischemic optic neuropathy (AION), drusen at the optic nerve head, chronic papilledema, juxtapapillary choroiditis and optic nerve head splinter hemorrhages (Tamm et al., 2013). Despite
1 About the Albert and Mary Lasker Foundation: Founded in 1942, the Albert and Mary Lasker Foundation envisions a healthier world through sustained support for basic and clinical medical research. The Foundation works to accomplish its mission through education and advocacy and, most notably, through a prestigious annual awards program. Lasker Award winners are selected by their peers, who, like themselves, include the world's most accomplished and well-respected medical research scientists, and thus the award represents a special honor. The Foundation's education and advocacy missions focus on engaging the public and policymakers on the importance of robust medical research programs and the funding to make them possible. The Lasker Foundation is also dedicated to supporting and inspiring the next generation of research scientists. For more information about the Lasker Foundation and its programs, visit http://www.laskerfoundation.org.
considerable research efforts over the past decades, our knowledge of the cellular and molecular mechanisms that cause glaucomatous optic nerve axonal degeneration at the ONH remains largely incomplete. The Lasker/IRRF Initiative for Innovation in Vision Science is a ten-year collaboration, launched in July 2008, between the Albert and Mary Lasker Foundation (Lasker)1 and the International Retinal Research Foundation (IRRF).2 The Initiative was designed to identify knowledge gaps in retinal and ophthalmic research and propose innovative strategies to accelerate the discovery of sight-saving treatments and prevention of retinal degenerative diseases using novel scientific, engineering and technological approaches. The Initiative's first report, Astrocytes and Glaucomatous Neurodegeneration, was published in November 2010 (a copy of the report is available at http://www.irrfonline.org/laskerirrf.html or http:// www.laskerfoundation.org/programs/irrf.htm). Since then, there is general agreement that significant scientific progress has occurred in the field. For example, it now is commonly accepted that astrocytes are a critical element of glaucoma pathophysiology, and advances in understanding the optic nerve head using new animal models have moved the field considerably. In 2014, the Initiative's Joint Advisory Board agreed that it would be valuable, both to the Initiative and to vision research, to evaluate where the field is now, whether and how the 2010 report stimulated innovative lines of research, what scientific hurdles have been overcome and what problems now confront the field. A Steering Committee was established to define goals and key issues for exploration by invited participants, which included many scientists from the first Initiative as well as some additional scientists. In March 2015, following an invitation by the Lasker/IRRF Initiative for Innovation in Vision Science, more than 40 scientists from all over the world met at the Howard Hughes Medical Institute Janelia Research Campus in Ashburn, Virginia (Fig. 1). They discussed the current status in the field and identified questions, topics and experiments that should be addressed within the next five years. The meeting format strongly emphasized discussion and 2 About the International Retinal Research Foundation: The International Retinal Research Foundation (IRRF) upholds a commitment to accelerate and sustain targeted research efforts into the diseases of the human eye, especially those affecting the retina and macula, to discover the causes, preventions, and cures of retinal and macular degenerative diseases and diabetic retinopathy. The IRRF accomplishes its mission by providing financial support for vision research directly, as well as through training fellowships, public awareness programs, and the promotion of the exchange of research findings. For more information about the IRRF, please visit www.irrfonline.org.
http://dx.doi.org/10.1016/j.exer.2017.02.013 0014-4835/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: Tamm, E.R., Dowling, J.E.Astrocytes and glaucomatous neurodegeneration, Experimental Eye Research (2017), http://dx.doi.org/10.1016/j.exer.2017.02.013
2
Editorial / Experimental Eye Research xxx (2017) 1e4
Fig. 1. Impressions from the March 2015 Lasker/IRRF Initiative for Innovation in Vision Science meeting “Astrocytes and Glaucomatous Neurodegeneration” at the Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia.
concentrated on questions within five general areas of research: 1. 2. 3. 4. 5.
Glial Cells, Ganglion Cells, and the Optic Nerve Head Astrocytes and Biomechanics Inflammation and Glaucomatous Neurodegeneration Optic Nerve Regeneration and Neurorepair Neuroprotection and What Is Needed Clinically
All areas were covered in presentations and keynote lectures followed by specific targeted sessions for which the steering committee had identified specific points for discussion. The ideas that came up at the targeted session were presented to all participants at the meeting and discussed. Finally, co-chairs and scribes summarized the results of each targeted session in five review articles that are now published in this special issue of Experimental Eye Research. The first article by Tamm and Ethier (2017, in press) reviews the possible molecular and cellular mechanisms that are behind axonal damage in glaucoma. An increase in strain of the peripapillary sclera that surrounds the ONH is identified as a possible initiating event that may trigger astrocyte reactivity in the ONH, putatively via transforming growth factor-b signaling. Reactive astrocytes in the ONH are expected to change homeostasis in the ONH microenvironment causing axonal degeneration. In a second article, by Stowell et al. (2017, in press), the current concepts on the biomechanical changes in the ONH and the exciting data that have been generated on this issue in the last few years are discussed. It is expected that more knowledge on the biomechanical forces that act on this tissue in the normal eye and in those with glaucoma is critical to understand the mechanisms that lead to structural changes at the ONH. An entirely novel concept to explain axonal damage in glaucoma is presented in a third article by Williams et al. (2017, in press). Here the available data that point to a neuroinflammatory origin of optic nerve damage in glaucoma are discussed and strategies are introduced that will help to explore this concept in more detail. Calkins et al. (2017, in press) provide a fourth article that highlights the available options to develop regenerative therapies for optic nerve axons that were damaged in glaucoma. They discuss the problems that need to be solved, such as preventing astrocyte reactivity and neuroinflammation at the ONH through which regenerating axons need to pass, but also the challenge to ensure that the connections with appropriate targets are formed in the brain. Finally, in a fifth article by Levin et al. (2017, in press), the requirements are discussed that are needed to initiate a neuroprotective therapy that will work not only in animal models with glaucoma,
but one that also has the potential to be translated into clinical practice. 2. Concluding Remarks As noted in the Concluding Remarks at the end of the Initiative's first report, glaucoma remains an intractable condition. But progress is being made, as detailed in this report; new ideas and approaches are being pursued and new facts and concepts elucidated. The energy, enthusiasm and imagination shown by the participants at the Janelia Research Campus meeting in March, 2015 bodes well for the future and for a breakthrough in dealing with this blinding disease. It is useful to note that glaucoma remains second on the list of blinding eye diseases in the United States, surpassed only by severe cataracts. Whereas some light perception remains in those suffering from severe cataracts, total blindness occurs in those with late-stage glaucoma. The need for a way to prevent glaucoma is very great, and the Lasker/IRRF Initiative hopes that the two meetings it has sponsored on glaucoma have helped get us closer to the day when this dreaded disease can be prevented. Steering committee John E. Dowling, Harvard University, Cambridge, MA, USA (Chair). Claude F. Burgoyne, Devers Eye Institute, Portland, OR, USA. David J. Calkins, Vanderbilt University, Nashville, TN, USA. Larry A. Donoso, Wills Eye Hospital & Jefferson Medical College, Philadelphia, PA, USA. Alan M. Laties, University of Pennsylvania, Philadelphia, PA, USA. al, QC, Canada. Leonard A. Levin, McGill University, Montre €t Erlangen-Nürnberg, Erlangen, Elke Lütjen-Drecoll, Universita Germany. Richard H. Masland, Harvard Medical School, Boston, MA, USA. Participants Larry Benowitz, Harvard Medical School, Boston, MA, USA. Alejandra Bosco, The University of Utah, Salt Lake City, UT, USA. Tailoi Chan-Ling, University of Sydney, Sydney, Australia. Francesca Cordeiro, University College, London, UK. Jonathan Crowston, University of Melbourne, Melbourne, Australia. John Danias, SUNY Downstate Medical Center, Brooklyn, NY,
Please cite this article in press as: Tamm, E.R., Dowling, J.E.Astrocytes and glaucomatous neurodegeneration, Experimental Eye Research (2017), http://dx.doi.org/10.1016/j.exer.2017.02.013
Editorial / Experimental Eye Research xxx (2017) 1e4
USA. al, QC, Canada. Adriana Di Polo, University of Montreal, Montre J. Crawford Downs, University of Alabama, Birmingham, AL, USA. Mark H. Ellisman, University of California San Diego, La Jolla, CA, USA. C. Ross Ethier, Georgia Institute of Technology and Emory University Medical School, Atlanta, GA, USA. Steven Fisher, University of California Santa Barbara, Santa Barbara, CA, USA. Brad Fortune, Devers Eye Institute, Portland, OR, USA. Marcus Fruttiger, University College, London, UK. Gareth Howell, The Jackson Laboratory, Bar Harbor, ME, USA. Andrew Huberman, Stanford University, Palo Alto, CA, USA. Tatjana C. Jakobs, Harvard Medical School, Boston, MA, USA. Elaine Johnson, Oregon Health and Science University, Portland, OR, USA. Markus Kuehn, University of Iowa, Iowa City, IA, USA. Geoffrey Lewis, University of California, Santa Barbara, Santa Barbara, CA, USA. Y. Joyce Liao, Stanford University, Palo Alto, CA, USA. Richard T. Libby, University of Rochester, Rochester, NY, USA. Richard Lu, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Nicholas Marsh-Armstrong, Johns Hopkins University, Baltimore, MD, USA. Claire H. Mitchell, University of Pennsylvania, Philadelphia, PA, USA. John Morrison, Oregon Health and Science University, Portland, OR, USA. Robert W. Nickells, University of Wisconsin-Madison, Madison, WI, USA. € teborg University, Milos Pekny, Sahlgrenska Academy at Go € teborg, Sweden. Go Hemali Phatnani, Columbia University, New York, NY, USA. Serge Przedborski Columbia University, New York, NY, USA. Harry A. Quigley, Johns Hopkins University, Baltimore, MD, USA. Martin Raff, University College, London, UK. Rebecca Sappington, Vanderbilt University, Nashville, TN, USA. Paul A. Sieving, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. Sansar Sharma, New York Medical College, Valhalla, NY, USA. Ian Sigal, University of Pittsburgh, Pittsburgh, PA, USA. Michael V. Sofroniew, University of California Los Angeles, Los Angeles, CA, USA. Alfred Sommer, Johns Hopkins University, Baltimore, MD, USA. Ernst R. Tamm, University of Regensburg, Regensburg, Germany. Ian Trounce, University of Melbourne, Melbourne, Australia. Lin Wang, Devers Eye Institute, Portland, OR, USA. Janey Wiggs, Harvard Medical School, Boston, MA, USA. Samuel Wu, Baylor College of Medicine, Houston, TX, USA. Don Zack, Johns Hopkins University, Baltimore, MD, USA. Scribes Melissa Cooper Vanderbilt University, Nashville, TN, USA. Megan Crowe, University of Wisconsin-Madison, Madison, WI, USA. Cheri Stowell, Devers Eye Institute, Portland, OR, USA. Peter Williams, The Jackson Laboratory, Bar Harbor, ME, USA. Collaborating executives Sandra Blackwood, Executive Director, International Retinal Research Foundation. Birmingham, AL, USA.
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Claire Pomeroy, President, Albert and Mary Lasker Foundation, New York, NY, USA. Acknowledgments The Initiative thanks the Boards of Directors of the Albert and Mary Lasker Foundation and the International Retinal Research Foundation for their support; the Initiative's Joint Advisory Board and Steering Committee, for their counsel; the session co-chairs who guided the development of the key issues discussed in this report and the scribes who recorded the discussions and drafted chapter texts; and all participants, for their energy, expertise, and lively discourse. Special thanks go to Karen M. Wright, Program Administrator for her diligent and essential administrative direction; to Kate Guthrie, Program Manager, for her logistical support; and to Sandra Blackwood, Executive Director of the IRRF, and Claire Pomeroy, President of Lasker, for their constancy and contributions to this endeavor. The Initiative gratefully acknowledges the Howard Hughes Medical Institute for its very generous in-kind contribution by making available the facilities at its Janelia Research Campus in Ashburn, Virginia, for the March 2015 meeting. Last but not least, we thank the Editor-in-Chief, Joe Hollyfield, and the publisher for giving us the opportunity to publish this Special Issue in Experimental Eye Research. References Boland, M.V., Ervin, A.M., Friedman, D.S., Jampel, H.D., Hawkins, B.S., Vollenweider, D., Chelladurai, Y., Ward, D., Suarez-Cuervo, C., Robinson, K.A., 2013. Comparative effectiveness of treatments for open-angle glaucoma: a systematic review for the U.S. Preventive Services Task Force. Ann. Intern Med. 158, 271e279. Calkins, D.J., Pekny, M., Cooper, M.L., Benowitz, L.I., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. The challenge of regenerative therapies for the optic nerve in glaucoma. Exp. Eye Res. http://dx.doi.org/10.1016/j.exer.2017.01.007 (in press). Collaborative Normal-Tension Glaucoma Study Group, 1998a. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am. J. Ophthalmol. 126, 487e497. Collaborative Normal-Tension Glaucoma Study Group, 1998b. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group Am. J. Ophthalmol. 126, 498e505. Foster, P.J., Buhrmann, R., Quigley, H.A., Johnson, G.J., 2002. The definition and classification of glaucoma in prevalence surveys. Br. J. Ophthalmol. 86, 238e242. Howell, G.R., Libby, R.T., Jakobs, T.C., Smith, R.S., Phalan, F.C., Barter, J.W., Barbay, J.M., Marchant, J.K., Mahesh, N., Porciatti, V., Whitmore, A.V., Masland, R.H., John, S.W., 2007. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J. Cell Biol. 179, 1523e1537. Kass, M.A., Heuer, D.K., Higginbotham, E.J., Johnson, C.A., Keltner, J.L., Miller, J.P., Parrish 2nd, R.K., Wilson, M.R., Gordon, M.O., 2002. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch. Ophthalmol. 120, 701e713 discussion 829e730. Kingman, S., 2004. Glaucoma is second leading cause of blindness globally. Bull. World Health Organ 82, 887e888. Leske, M.C., Heijl, A., Hussein, M., Bengtsson, B., Hyman, L., Komaroff, E., 2003. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch. Ophthalmol. 121, 48e56. Levin, L.A., Quigley, H.A., Crowe, M.E., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. Neuroprotection for glaucoma: requirements for clinical translation. Exp. Eye Res. http://dx.doi.org/ 10.1016/j.exer.2016.12.005 (in press). Quigley, H.A., 2011. Glaucoma. Lancet 377, 1367e1377. Quigley, H.A., Addicks, E.M., Green, W.R., Maumenee, A.E., 1981. Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch. Ophthalmol. 99, 635e649. Quigley, H.A., Broman, A.T., 2006. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 90, 262e267. Resnikoff, S., Pascolini, D., Etya'ale, D., Kocur, I., Pararajasegaram, R., Pokharel, G.P., Mariotti, S.P., 2004. Global data on visual impairment in the year 2002. Bull. World Health Organ 82, 844e851. Stowell, C., Burgoyne, C., Tamm, E.R., Ethier, C.R., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. Biomechanical aspects of axonal damage in glaucoma: a brief review. Exp. Eye Res. http://
Please cite this article in press as: Tamm, E.R., Dowling, J.E.Astrocytes and glaucomatous neurodegeneration, Experimental Eye Research (2017), http://dx.doi.org/10.1016/j.exer.2017.02.013
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dx.doi.org/10.1016/j.exer.2017.02.005 (in press). Tamm, E.R., Ethier, C.R., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. Biological aspects of axonal damage in glaucoma: a brief review. Exp. Eye Res. http://dx.doi.org/10.1016/ j.exer.2017.02.006 (in press). Tamm, E.R., Schmetterer, L., Grehn, F., 2013. Status and perspectives of neuroprotective therapies in glaucoma: the European glaucoma society white paper. Cell Tissue Res. 353, 347e354. Tham, Y.C., Li, X., Wong, T.Y., Quigley, H.A., Aung, T., Cheng, C.Y., 2014. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 121, 2081e2090. The AGIS Investigators, 2000. The advanced glaucoma intervention study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am. J. Ophthalmol. 130, 429e440. Williams, P.A., Marsh-Armstrong, N., Howell, G.R., The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants, 2017. Neuroinflammation in glaucoma: a new opportunity. Exp. Eye Res. http://dx.doi.org/ 10.1016/j.exer.2017.02.014 (in press).
Ernst R. Tamm, M.D., Professor and Chairman* Institute of Human Anatomy & Embryology, University of Regensburg, €tsstr. 31, D-93053 Regensburg, Germany Universita John E. Dowling, PhD., Gordon and Llura Gund Research Professor of Neurosciences NWL-347.2 Harvard University, 52 Oxford Street, Cambridge, MA 02138, United States E-mail address: [email protected]. * Corresponding author. E-mail address: [email protected] (E.R. Tamm).
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Please cite this article in press as: Tamm, E.R., Dowling, J.E.Astrocytes and glaucomatous neurodegeneration, Experimental Eye Research (2017), http://dx.doi.org/10.1016/j.exer.2017.02.013