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Glaucoma: Translating science into solutions

Professor Sir Peng T Khaw

The research topics of Peng Khaw

As an undergraduate, I was very interested in general medicine and ophthalmology so, when I graduated from medical school, I trained in both general medicine and ophthalmology.  Ophthalmology ultimately prevailed, as it has the wonderful combination of medicine and science, coupled with technical and surgical innovation, all coming together to offer the prospect of transforming lives.  Glaucoma increasingly fascinated me, as an enigmatic disease, which currently affects more than 70 million people, of whom more than 7 million are bilaterally blind.

My dedication to this area of ophthalmology was cemented when I came to Moorfields as a Senior Trainee Ophthalmologist, first under Roger Hitchings, and then Noel Rice. I saw many patients with severe glaucoma. In particular, I still recall one child who I looked after, who eventually lost all her sight due to the failure of every operation we carried out on her, due to scarring.  At the end of my clinical training, I was fortunate to get a Wellcome Trust Clinician Scientist Fellowship, which allowed me to enter the laboratory and acquire the cellular and molecular tools to investigate tissue repair under Ian Grierson at the UCL Institute of Ophthalmology in London, and at the University of Florida with Gregory Schultz.

Understanding ocular wound healing, and the effects and delivery of wound modulating agents

The processes involved in tissue repair and scarring are very important in the eye.  Scarring processes play a part in the pathogenesis or failure of treatment of virtually every major blinding disease in the world today.  When I started my Fellowship, I began investigating the major factors in aqueous that were stimulating the conjunctival fibroblast to create scar tissue. We looked at the major growth factors in aqueous that we could assay at the time and, although most of them stimulated a variety of fibroblast activities including proliferation, migration, collagen production and contraction, one growth factor stood out because of the magnitude of activity; that was transforming growth factor beta. We used a variety of antagonistic agents to transforming growth factor beta. This included humanised antibodies to transforming growth factor beta 2, which were just being produced by Cambridge Antibody Technology, based on Greg Winter’s novel humanised antibody technology. We conducted in vitro and in vivo experiments, and ultimately a large Phase III international trial, but unfortunately this did not show statistically significant differences between the antibody and placebo. It is now clear that antibodies in the subconjunctival space undergo very rapid dissolution with so-called first order pharmacokinetics, so the majority of antibody is dispersed within half an hour. This led us to investigate better methods of prolonging drug delivery or agents that work for longer.

We also started working with other agents, including a variety of matrix metalloproteinase protein inhibitors. We were one of the first groups to determine the importance of matrix metalloproteinases in cell-mediated collagen contraction, and that inhibiting these enzymes reduces contraction. Fibroblast-mediated collagen contraction is a very important contributory factor in the failure of glaucoma surgery. The role of cytoskeletal elements within the cell are also a critical component of this contraction and, with Maryse Bailly, we have developed a living tissue model of this process. Another critical component of the scarring process is inflammation, and it became clear that the inflammatory cells, particularly macrophages, were resulting in a persistent scarring response. This occurs in part because of the interaction between the inflammatory cells and the fibroblasts. Again, a variety of anti-inflammatory agents could modulate this process. However, all these key processes and components overlap and persist. Examination of the protein levels in aqueous showed that, in situations where the blood aqueous barrier breakdown was prolonged, this was associated with a much worse prognosis for healing and surgical failure. Therefore, one of the biggest challenges has been appropriate longer-term drug delivery without requiring a large number of injections. Working with Steve Brocchini at the UCL School of Pharmacy, we have been developing better pharmacokinetic models, including  novel anterior segment and whole eye models (the PK eye TM) to develop different methods of slow release of small molecules and also antibodies.

Very early on, we also investigated the effects of anticancer agents on fibroblasts and cellular activity related to scarring. The Fluorouracil Filtering Surgery Study group in Miami had pioneered the use of 5FU injections (initially 21 injections over 14 days) following some initial work done on proliferative vitreoretinopathy. Dr Chen in Taiwan pioneered the use of single dose mitomycin-C, based on the principle that a scarring wound was in some ways similar to a tumour with the loss of various aspects of cellular control. We discovered in cell culture that we could achieve the long-term arrest of many weeks of several of the activities which caused scarring, including proliferation, migration and contraction. With the appropriate control of the concentration, the time of exposure could be brought down to just a few minutes. This was associated with long-term cell protective mechanisms, such as p53 induction. We modelled the cellular and regional effects, and found them to be localised, a very important finding that is still relevant today. We also established the pharmacokinetic principles showing a plateau effect after about 3 minutes of tissue exposure. The basis of these findings help govern how we best use single application antimetabolites today.

The early use of antimetabolites, particularly mitomycin-C (MMC), was associated with very thin cystic conjunctival drainage areas or blebs after glaucoma surgery, which had a high incidence of inflammation (blebitis) or intraocular infection (endophthalmitis). Initially, ophthalmologists reacted by reducing the size of the sponge application. However, based on clinical observation and laboratory modelling, we proposed the concept of a  local ring of scar tissue (“ring of steel”), based on our finding of very localised effects together with anterior limbal aqueous drainage, which led to these cystic blebs. We therefore proposed the opposite strategy to others, a much larger area of MMC application, and the construction of a scleral flap so that aqueous drained posteriorly. This had a dramatic effect on the incidence of bleb-related complications and, together with techniques such as tighter adjustable/releasable sutures, have considerably increased the short and long-term safety of trabeculectomy. Trabeculectomy is still the most commonly performed operation worldwide due to the low cost of the operation. The principles of controlled posterior fluid and the large surface area of MMC treatment are incorporated in some of the latest and most successful micro drainage devices currently being tested.

Our ability to perform surgery more successfully, to better control flow with an increased understanding of how to modulate scarring successfully has increased the prospect of achieving safe maximal lowering of intraocular pressure for long durations.  Despite the huge numbers of patients with glaucoma, particularly in the poorer parts of the world, glaucoma has not been accorded the same priority as other diseases such as cataract or trachoma, because it lacks a treatment that can be delivered quickly and safely. Given that intraocular pressures in the low teens are associated with minimal progression of glaucoma, I have proposed the 10 10 10 target for glaucoma. That is a pressure of 10mmHg for 10 years done in 10 minutes with a low complication rate much less than cataract.  This provides us with a highly ambitious but achievable goal to advocate for glaucoma to be a treatment priority around the world.  Given that this disease is estimated to affect 111 million people within a few decades, this is a target we must strive to achieve to prevent millions of people around the world being blind.  With further research continuing in both the academic and commercial sectors, this , target is now coming within our reach.

Maintenance of tissues in the retina and optic nerve in glaucoma

Apart from lowering the intraocular pressure, there still remains the tantalising issue of the basic pathogenesis of the axonal damage that occurs in glaucoma and whether there might be a way of halting deterioration and even improving function in glaucoma – this is the other holy grail.  With Astrid Limb’s group, we have been working on various cellular strategies. The discovery of the multipotent Müller cell lines which we named after Moorfields and the UCL Institute of Ophthalmology (the MIO-M1 line) and the method of isolating them from donor eyes, even very aged eyes over 90 years, provide a potent tool to investigate cellular intervention.  These unique glial cells that have so many key functions in the retina,  including their ability to regenerate the retina in zebrafish but unfortunately not in man. However, given appropriate conditions, the Müller cells are able to differentiate into many different retinal cell types. These cells are able to support the damaged ganglion cells and axons in a model of damage with preservation of the suprathreshold response on electrophysiological testing.  With Geoff Raisman and Ying Li, the changes at the optic nerve head of the rat were examined using a microbead model of raised pressure.  It is well known that the rat has no lamina cribrosa, but the axons appear to die in a similar way to the primate when the intraocular pressure is raised.  The key anatomical event appears to be the separation of the astrocytes from the axons resulting in a focal loss of cellular support for the axon.  A simple term has been coined for this phenomenon which is the “Energy Theory” of glaucoma.

However, implicit in this term probably lies a complex neurometabolic support system including energy substrates, ion homeostasis, neurotrophic stimulation, autophagy and a physical support system provided by the glial cells to the axons. The astrocytes in the optic nerve head and the other glia, including primarily the Müller cells in the retina, which have the same embryonic lineage as the astrocytes.  Given that the energy requirements of the nonmyelinated part of the axons from the back of the optic nerve to the ganglion cell body are many times higher, the high metabolic activity of the glial cells including the presence of giant mitochondria in the cell with close glial contact with virtually all the nonmyelinated axons.  In the optic nerve head, the astrocytes are at a particular disadvantage in being positioned across the line of force of intraocular pressure, as opposed to retinal Müller cells which are vertical. This makes them particularly susceptible to displacement and dissociation from the axons, which helps to explain the particular susceptibility of the axons within optic nerve head. Even in the primate, with the strengthened lamina tissues, any human tissue subjected to the constant pulsations of the eye will eventually deteriorate unless maintained by cellular activity, which requires energy. Within the nerve head the primary support cell is the astrocyte.  Although evolving, this concept helps us after many years of seeing all types of patients.   It helps us begin to understand many aspects of the group of conditions called glaucoma from the increase in glaucoma with age, to the many different clinical manifestations including the symptoms, all typified by damage at the optic nerve head and subsequent damage to the axons and the Ganglion cell bodies.   More exciting it also suggests that replacement with specialist “high energy” glial cells such as Muller or olfactory unsheathing cells have the potential to at least stabilise and possibly even improve nerve function in glaucoma damage, something we could only dream about previously.

Conclusion

For me and my colleagues and patients, research offers the prospect of advances in glaucoma and all of ophthalmology.  I could only have dreamt about these advances when I first ventured into Ophthalmology.  I made the right decision.  Even in these very challenging times, the prospect for vision research changing and improving millions of peoples lives around the world for the better has never been greater.

Some References

  1. Grant MB, Khaw PT, Schultz GS, Adams JL, Shimizu RW. Effects of epidermal growth factor, fibroblast growth factor, and transforming growth factor-beta on corneal cell chemotaxis. Invest Ophthalmol Vis Sci. 1992 Nov;33(12):3292-301.
  2. Occleston NL, Alexander RA, Mazure A, Larkin G, Khaw PT. Effects of single exposures to antiproliferative agents on ocular fibroblast-mediated collagen contraction. Invest Ophthalmol Vis Sci. 1994 Sep;35(10):3681-90.
  3. Cordeiro MF, Bhattacharya SS, Schultz GS, Khaw PT. TGF-beta1, -beta2, and-beta3 in vitro: biphasic effects on Tenon's fibroblast contraction, proliferation, and migration. Invest Ophthalmol Vis Sci. 2000 Mar;41(3):756-63.
  4. Mead AL, Wong TT, Cordeiro MF, Anderson IK, Khaw PT. Evaluation ofanti-TGF-beta2 antibody as a new  postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3394-401.
  5. CAT-152 0102 Trabeculectomy Study Group, Khaw PT, Grehn F, Holló G, Overton B,  Wilson R, Vogel R, Smith Z. A phase III study of subconjunctival human anti-transforming growth factor beta(2) monoclonal antibody (CAT-152) to prevent  scarring after first-time trabeculectomy. Ophthalmology. 2007 Oct;114(10):1822-30.
  6. Daniels JT, Cambrey AD, Occleston NL, Garrett Q, Tarnuzzer RW, Schultz GS, Khaw PT. Matrix metalloproteinase inhibition modulates fibroblast-mediated matricontraction and collagen production in vitro. Invest Ophthalmol Vis Sci. 2003 Mar;44(3):1104-10.
  7. Daniels JT, Schultz GS, Blalock TD, Garrett Q, Grotendorst GR, Dean NM, Khaw PT. Mediation of transforming growth factor-beta(1)-stimulated matrix contraction by fibroblasts: a role for connective tissue growth factor in contractile scarring. Am J Pathol. 2003 Nov;163(5):2043-52.
  8. Wong TT, Sethi C, Daniels JT, Limb GA, Murphy G, Khaw PT. Matrix metalloproteinases in disease and repair processes in the anterior segment. Surv Ophthalmol. 2002 May-Jun;47(3):239-56. Review.
  9. Wong TT, Mead AL, Khaw PT. Matrix metalloproteinase inhibition modulates postoperative scarring after experimental glaucoma filtration surgery. Invest Ophthalmol Vis Sci. 2003 Mar;44(3):1097-103.
  10. Sheridan CM, Occleston NL, Hiscott P, Kon CH, Khaw PT, Grierson I. Matrix metalloproteinases: a role in the contraction of vitreo-retinal scar tissue. Am J Pathol. 2001 Oct;159(4):1555-66.
  11. Yu-Wai-Man C, Treisman R, Bailly M, Khaw PT. The role of the MRTF-A/SRF pathway in ocular fibrosis. Invest Ophthalmol Vis Sci. 2014 Jul 23;55(7):4560-7.
  12. Yu-Wai-Man C, Tagalakis AD, Manunta MD, Hart SL, Khaw PT. Receptor-targeted liposome-peptide-siRNA nanoparticles represent an efficient delivery system for MRTF silencing in conjunctival fibrosis. Sci Rep. 2016 Feb 24;6:21881.
  13. Chang L, Crowston JG, Cordeiro MF, Akbar AN, Khaw PT. The role of the immune system in conjunctival wound healing after glaucoma surgery. Surv Ophthalmol. 2000 Jul-Aug;45(1):49-68. Review..
  14. Crowston JG, Salmon M, Khaw PT, Akbar AN. T-lymphocyte-fibroblast interactions. Biochem Soc Trans. 1997 May;25(2):529-31. Review.
  15. Shaunak S, Thomas S, Gianasi E, Godwin A, Jones E, Teo I, Mireskandari K, Luthert P, Duncan R, Patterson S, Khaw PT, Brocchini S. Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation.  Nat Biotechnol. 2004 Aug;22(8):977-84. Epub 2004 Jul 18.
  16. Siriwardena D, Kotecha A, Minassian D, Dart JK, Khaw PT. Anterior chamber flare after trabeculectomy and after phacoemulsification. Br J Ophthalmol. 2000 Sep;84(9):1056-7.
  17. Awwad S, Lockwood A, Brocchini S, Khaw PT. The PK-Eye: A Novel In Vitro Ocular Flow Model for Use in Preclinical Drug Development. J Pharm Sci. 2015 Oct;104(10):3330-42.
  18. Khaw PT, Sherwood MB, MacKay SL, Rossi MJ, Schultz G. Five-minute treatments with  fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenon's capsule fibroblasts. Arch Ophthalmol. 1992 Aug;110(8):1150-4.
  19. Khaw PT, Doyle JW, Sherwood MB, Grierson I, Schultz G, McGorray S. Prolonged localized tissue effects from 5-minute exposures to fluorouracil and mitomycin C. Arch Ophthalmol. 1993 Feb;111(2):263-7.
  20. Smith MF, Sherwood MB, Doyle JW, Khaw PT. Results of intraoperative 5-fluorouracil supplementation on trabeculectomy for open-angle glaucoma. Am J Ophthalmol. 1992 Dec 15;114(6):737-41..
  21. Wells AP, Crowston JG, Marks J, Kirwan JF, Smith G, Clarke JC, Shah R, VieiraJ, Bunce C, Murdoch I, Khaw PT. A pilot study of a system for grading of drainage blebs after glaucoma surgery. J Glaucoma. 2004 Dec;13(6):454-60..
  22. Wells AP, Cordeiro MF, Bunce C, Khaw PT. Cystic bleb formation and related complications in limbus- versus fornix-based conjunctival flaps in pediatric and young adult trabeculectomy with mitomycin C. Ophthalmology. 2003  Nov;110(11):2192-7.
  23. Samsudin A, Eames I, Brocchini S, Khaw PT. The Influence of Scleral Flap Thickness, Shape, and Sutures on Intraocular Pressure (IOP) and Aqueous Humor Flow Direction in a Trabeculectomy Model. J Glaucoma. 2016 Jul;25(7):e704-12.
  24. Jayaram H, Scawn R, Pooley F, Chiang M, Bunce C, Strouthidis NG, Khaw PT, Papadopoulos M. Long-Term Outcomes of Trabeculectomy Augmented with Mitomycin C Undertaken within the First 2 Years of Life. Ophthalmology. 2015  Nov;122(11):2216-22.
  25. Wong TT, Khaw PT, Aung T, Foster PJ, Htoon HM, Oen FT, Gazzard G, Husain R, Devereux JG, Minassian D, Tan SB, Chew PT, Seah SK. The singapore 5-Fluorouracil trabeculectomy study: effects on intraocular pressure control and disease progression at 3 years. Ophthalmology. 2009 Feb;116(2):175-84.
  26. Limb GA, Salt TE, Munro PM, Moss SE, Khaw PT. In vitro characterization of a spontaneously immortalized human Müller cell line (MIO-M1). Invest Ophthalmol Vis Sci. 2002 Mar;43(3):864-9.
  27. Lawrence JM, Singhal S, Bhatia B, Keegan DJ, Reh TA, Luthert PJ, Khaw PT, Limb GA. MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics. Stem Cells. 2007 Aug;25(8):2033-43.
  28. Li Y, Li D, Ying X, Khaw PT, Raisman G. An energy theory of glaucoma. Glia. 2015 Sep;63(9):1537-52. doi: 10.1002/glia.22825. Epub 2015 Mar 23.
  29. Dai C, Khaw PT, Yin ZQ, Li D, Raisman G, Li Y. Olfactory Ensheathing Cells Rescue Optic Nerve Fibers in a Rat Glaucoma Model. Transl Vis Sci Technol. 2012 Aug 24;1(2):3.
  30. Singhal S, Bhatia B, Jayaram H, Becker S, Jones MF, Cottrill PB, Khaw PT, Salt TE, Limb GA. Human Müller glia with stem cell characteristics differentiate into retinal ganglion cell (RGC) precursors in vitro and partially restore RGC function in vivo following transplantation. Stem Cells Transl Med. 2012Mar;1(3):188-99.
  31. Becker S, Eastlake K, Jayaram H, Jones MF, Brown RA, McLellan GJ, Charteris DG, Khaw PT, Limb GA. Allogeneic Transplantation of Müller-Derived Retinal Ganglion Cells Improves Retinal Function in a Feline Model of Ganglion Cell Depletion. Stem Cells Transl Med. 2016 Feb;5(2):192-205.
  32. Singhal S, Lawrence JM, Bhatia B, Ellis JS, Kwan AS, Macneil A, Luthert PJ, Fawcett JW, Perez MT, Khaw PT, Limb GA. Chondroitin sulfate proteoglycans and microglia prevent migration and integration of grafted Müller stem cells into degenerating retina. Stem Cells. 2008 Apr;26(4):1074-82.

Biographical Note

Professor Sir Peng Tee Khaw is Professor of Glaucoma and Ocular Healing and Consultant Ophthalmic Surgeon; He is also Director of the National Institute for Health Research Biomedical Research Centre Moorfields Eye Hospital and UCL Institute of Ophthalmology, United Kingdom and Director of Research and Development at Moorfields Eye Hospital.  He was formerly President of ARVO.  He is a Fellow of the British Academy of Medical Sciences and an NIHR Senior Investigator. He has helped to raise over US$150 million for clinical and basic research and facilities, including the Richard Desmond Children’s Eye hospital, and the NIHR clinical research centre at Moorfields, which are both the largest in the world.

In 2013, he was knighted in the Queen’s Birthday Honours for services to ophthalmology.

Professor Sir Peng T Khaw

PhD FRCP FRCS FRCOphth FRCPath FCOptom  Hon DSc CBiol FRSB FARVO FMedSci
Professor of Glaucoma and Ocular Healing, and Consultant Ophthalmic Surgeon

Director:
National Institute for Health Research Biomedical Research Centre for Ophthalmology
Moorfields Eye Hospital UCL Institute of Ophthalmology
Eyes and Vision Programme, UCL Partners Academic Health Science Centre
Research and Development, Moorfields Eye Hospital

Contact

Mail:
UCL Institute of Ophthalmology and Moorfields Eye Hospital
11-43 Bath Street,
London EC1V 9EL,
United Kingdom

Phone and E-mail
Clinical:
Tel: +44 (0)20 7566 2334
E-mail: peng.khaw[at]moorfields.nhs.uk

Academic:
Tel: +44 (0)20 7608 6887
E-mail: p.khaw[at]ucl.ac.uk