John van Geest Centre for Brain Repair

School of Clinical Medicine

Sections

 

In this section

 

Keith Martin

Screen shot 2013-09-04 at 14.18.54Keith Martin, MA DM MRCP FRCOphth

Professor of Ophthalmology, University of Cambridge

Honorary Consultant Ophthalmic Surgeon, Addenbrooke’s Hospital, Cambridge

E-mail address: krgm2@cam.ac.uk

 

 Biosketch

Keith Martin is Professor of Ophthalmology at the University of Cambridge. He is also Clinical Director for Ophthalmology and Lead Clinician for Glaucoma at Cambridge University Hospitals NHS Foundation Trust.

Keith Martin graduated with first class honours in Neuroscience from Cambridge University in 1990 and from Oxford University Clinical School in 1993.   He trained in general medicine and neurology at the Hammersmith Hospital and the National Hospital for Neurology & Neurosurgery in London and the John Radcliffe Hospital in Oxford. His Higher Specialist Training in Ophthalmology was undertaken in Cambridge before three years of Research and Clinical Fellowship Training in glaucoma with Harry Quigley at the Wilmer Eye Institute, Johns Hopkins University, Baltimore, USA and Peng Khaw at the Institute of Ophthalmology, London.

He established the Glaucoma Research Laboratory at the Cambridge University Centre for Brain Repair in 2005 to study the mechanisms of retinal ganglion cell death in glaucoma and to develop new treatment approaches using stem cells, gene therapy and other techniques.

Professor Martin was awarded the ARVO Foundation for Eye Research / Carl Camras Translational Research Award for 2010 and the National Centre for the Refinement, Replacement and Reduction of Animals in Research Prize 2009. He also received the World Glaucoma Association Senior Clinician Scientist Award in 2011.

Clinically, he specialises in the medical and surgical management of complex glaucoma in adults and children, particularly uveitic glaucoma. He is the Basic Science Section Co-Editor of the Journal of Glaucoma and the Treasurer of the World Glaucoma Association.

Research interests

Glaucoma

Glaucoma is the commonest cause of irreversible blindness in the world. The condition involves progressive death of retinal ganglion cells in the eye resulting in irreversible visual loss. Recent evidence suggests that neuronal death in glaucoma shares mechanisms with other neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease. Thus, advances in our understanding of glaucoma may have implications for other brain diseases and vice versa.

We now have effective treatments that can dramatically slow the progress of glaucoma by lowering eye pressure. However, as the onset and progression of glaucoma are frequently asymptomatic, this detectable and treatable disease remains the leading cause of irreversible blindness worldwide. In addition, some people with severe glaucoma continue to deteriorate even when very low eye pressure is achieved.

For the large numbers of individuals already blind or severely visually impaired due to glaucoma, conventional treatment offers no chance of visual improvement. This highlights a pressing need for new therapies directed at slowing the death of RGC and replacing them once they have been lost. In addition, there are many other examples of optic nerve pathologies, including optic nerve trauma, Leber’s hereditary optic neuropathy and ischaemic optic neuropathy, where no currently available treatment can improve vision once it has been lost. Thus, the clinical need for new techniques of optic nerve restoration is indisputable. Death of retinal ganglion cells (RGC) is the principal pathological finding in glaucoma, leading to progressive visual field loss and eventually to blindness.

Elevated intraocular pressure (IOP) is by far the most important risk factor for the development and progression of glaucoma. IOP-lowering treatment is therefore the current mainstay of glaucoma treatment. However, some patients with glaucoma worsen and go blind despite maximal IOP reduction. The raised IOP may therefore initiate a neurodegenerative process in RGC that is not stopped by present glaucoma treatments. At present, there is no available treatment that can restore visual function once RGC have died.

An important goal of our group is to understand better the mechanisms of RGC death in glaucoma, to develop methods to protect RGC thus slowing the progression of glaucomatous visual loss, and ultimately to restore vision in those blind due to the disease.

We have developed a novel model of glaucoma that has proven to be very useful in the investigation of glaucoma pathogenesis. The model allows RGC death to be studied both during the period of increased IOP and after IOP has fallen back to normal levels. Using this model, we have demonstrated potentially important changes in retinal glutamate transporters occuring as a specific response to elevated intraocular pressure, suggesting a new target for glaucoma therapy in the future.

Current projects

1. Stem cells as a potential treatment for glaucoma

We are actively investigating the ability of different types of stem cell to integrate into the glaucomatous retina. Current cells of interest include oligodendrocyte precursor cells, mesenchymal stem cells and Muller stem cells derived from the adult human retina. We have developed a novel retinal explant model which has allowed us to gain new insights into the barriers to the survival, migration and integration of transplanted cells. We are also using what is known about the control of retinal neurogenesis during development to develop methods to control the differentiation of donor cells prior to transplantation into the diseased retina.

2. Mechanisms of axonal injury in glaucoma

Axonal injury appears an important trigger of axonal and cell body degeneration in glaucoma and other neurodegenerative diseases.  We have recently discovered that the Wallerian degeneration slow (WldS) mutation can delay optic nerve degeneration in a model of glaucoma. Axonal degeneration must be prevented for the optic nerve to remain functional, so in our current work we are looking for ways to pharmacologically mimic and enhance the protective mechanism of WldS. We hope this approach will offer an important route towards new treatments for glaucoma and other neurodegenerative diseases.

3. The role of disrupted axonal transport in glaucoma

Our previous work suggests that elevated IOP causes interruption to retrograde axonal transport at the level of the optic nerve head. Dynein, the motor protein responsible for most retrograde axonal transport, accumulates at the optic nerve head in animal models of glaucoma. We are exploring the nature of the transport block in glaucoma and developing new imaging methods to allow the study of axonal transport in vivo in the living eye. We are currently using a wide range of techniques including time lapse imaging of cellular transport and engineered channels produced in collaboration with the Department of Physics. We are also using molecular biological techniques to probe the early changes that occur in response to elevated eye pressure to try to find new treatment approaches.

4. Neurotrophic factor therapy for glaucoma

We have previously pioneered new methods for highly efficient gene transfer to RGC. Using adeno-associated virus mediated expression of brain-derived neurotrophic factor, we were first in the world to demonstrate a protective effect of neurotrophic factor gene therapy in a model of glaucoma. We have recently identified a neurotrophic factor pathway, platelet derived growth factor (PDGF) that appears key to mediating the neuroprotective effect of mesenchymal stem cells in experimental models relevant to glaucoma. Planned work with further explore the effects of modulation of this pathway as a potential treatment for glaucoma.

5. Improving RPE cell transplantation by modulation of integrins

Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the developed world. As failure of the retinal pigment epithelial (RPE) layer of the retina appears to be the root cause of AMD in many patients, cell transplantation is an attractive strategy, particularly at the stage of the disease where significant RPE loss has occurred but photoreceptor loss is less severe. Our work suggests that manipulation of RPE cell integrin through integrin activating strategies, and/or expression of new integrin subunits such as alpha9 could be effective in improving the efficacy of RPE cell transplantation in AMD-affected eyes, allowing the cells to adhere and migrate on pathological Bruch’s membrane. We are currently testing this approach in in vivo models with Bruch’s membrane pathology relevant to AMD.

6. Role of activated retinal glia in survival and regeneration of retinal neurons

The aim of this project is to increase our understanding of the fundamental mechanisms underpinning neuronal survival and axon regeneration in the injured CNS.

Research by Barbara Lorber in our laboratory has shown that activated retinal glia are potentially very important positive mediators of successful RGC axon regeneration in the lesioned optic nerve, and also mediate survival and regenerative processes in experimental glaucoma, pointing to a similar underlying mechanism in these two models of optic nerve injury and disease. Current work aims to further clarify the regenerative role of retinal glia activation in CNS injury and disease models and investigate the growth factor expression profile of activated retinal glia via state-of-the-art proteomic methods. A further aim is to evaluate if optimising delivery of identified growth factors via gene delivery at the site of the cell body/glial scar can stimulate neuronal survival and axon regeneration in glaucoma, optic nerve and spinal cord injury models. This work has the potential to develop new clinical therapies for the treatment of blindness and the repair of damaged CNS tracts after spinal cord and brain injury.

Research Group

Post-doctoral scientists:

  • Dr Amanda Barber, PhD
  • Dr Andrew Osborne, PhD
  • Dr Barbara Lorber, PhD
  • Dr Natalie Bull, PhD  (2005-2012)
  • Dr Andrew White, MD PhD (2010-2)
  • Dr Christian Noack, MD PhD (2006-8)
  • Dr Sarah Hughes, PhD (2005-6)
  • Dr Nephtali Marina Gonzalez, MD PhD (2007-8)

PhD students:

  • Rachel Chong (2012 -)
  • Alessia Tasoni (2010 -)
  • Janosch Heller (co-supervisor 2009 -)
  • Alex Hyatt, PhD (2007- 10)
  • Thomas V Johnson, PhD (2006-2010)
  • Bogdan Beirowski, PhD (co-supervisor 2006-8)

Research Nurse:

  • Debbie Jankowski

Clinical and Research Fellows:

  • Simon Skalicky (2013-)
  • Humma Shahid (2011-)
  • Andrew White (2010-12)
  • John Landers (2009-10)

Academic Clinical Fellow

  • Jonathan Roos (2011-)

Collaborators

  • Dr Michael Coleman, Babraham Institute, Cambridge (transgenic models to study optic nerve disease)
  • Professor Robin Franklin (oligodendrocyte precursor cells)
  • Dr Maria Grazia Spillantini (Tau changes in glaucoma)
  • Professor James Fawcett (barriers to migration and integration of retinal transplants)
  • Dr Aviva Tolkovsky, Centre for Brain Repair, Cambridge (non-apoptotic mechanisms of neuronal death and neuronal autophagy)
  • Dr Astrid Limb and Professor Peng Khaw, Institute of Ophthalmology, London (Müller stem cell lines)
  • Professor Eugene Terentjev, Department of Physics, University of Cambridge (engineered axonal growth conduits)
  • Prof Elena Vecino, University of Salamanca, Spain (axonal transport)
  • Prof Ken Smith, University College London (neuroprotective strategies)
  • Dr Julie Sanderson, University of East Anglia (human retinal explants)

Selected recent publications

Johnson TV, DeKorver NW, Levasseur V, Osborne A, Tassoni A, Lorber B, Heller JP, Villasmil R, Bull ND, Martin KR*, Tomarev SI*. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor (PDGF) through analysis of the mesenchymal stem cell secretome. Brain 2013 (in press)

Zhekov I, Janjua R, Shahid H, Sarkies N, Martin KR, White AJ. A retrospective analysis of long-term outcomes following a single episode of transscleral cyclodiode laser treatment in patients with glaucoma. BMJ Open. 2013 Jul 6;3(7). doi:pii: e002793. 10.1136/bmjopen-2013-002793. Print 2013. PMID: 23833142

Khandhadia S, Hakobyan S, Heng LZ, Gibson J, Adams DH, Alexander GJ, Gibson JM, Martin KR, Menon G, Nash K, Sivaprasad S, Ennis S, Cree AJ, Morgan BP, Lotery AJ. Age-related Macular Degeneration and Modification of Systemic Complement Factor H Production Through Liver Transplantation. Ophthalmology. 2013 Apr 3. doi:pii: S0161-6420(13)00006-7. 10.1016/j.ophtha.2013.01.004. PMID: 23562165

White AJ, Mukherjee A, Hanspal I, Sarkies NJ, Martin KR, Shah P. Acute transient corneal endothelial changes following selective laser trabeculoplasty. Clin Experiment Ophthalmol. 2012 Oct 19. doi: 10.1111/ceo.12022. [Epub ahead of print]PMID: 23078238

Landers J, Martin KR, Sarkies N, Bourne R, Watson P. Author reply: A Twenty-Year Follow-up Study of Trabeculectomy Ophthalmology. 2012 Oct;119(10):2195-6. doi: 10.1016/j.ophtha.2012.05.006. PMID: 23034298

Marina N, Sajic M, Bull ND, Hyatt AJ, Berry D, Smith KJ, Martin KR. Lamotrigine monotherapy does not provide protection against the loss of optic nerve axons in a rat model of ocular hypertension. Exp Eye Res. 2012 Sep 13. pii: S0014-4835(12)00273-4. doi: 10.1016/j.exer.2012.09.002. [Epub ahead of print] PMID: 22982756

Johnson TV, Martin KR. Cell transplantation approaches to retinal ganglion cell neuroprotection in glaucoma. Curr Opin Pharmacol. 2012 Aug 29. [Epub ahead of print] PMID: 22939899

Lorber B, Tassoni A, Bull ND, Moschos MM, Martin KR. Retinal ganglion cell survival and axon regeneration in WldS transgenic rats after optic nerve crush and lens injury. BMC Neurosci. 2012 Jun 6;13(1):56.

Bull ND, Chidlow G, Wood J, Martin KR, Casson RJ. The mechanism of axonal degeneration after perikaryal excitotoxic injury to the retina. Experimental Neurology 2012, Epub Apr 5. PMID: 22504112

Bull ND, Guidi A, Goedert M, Martin KR*, Spillantini MG*. Reduced axonal transport in the human P301S tau transgenic mouse enhances optic nerve neurodegeneration. PLoS ONE 2012; 7(4): e34724. doi:10.1371/journal.pone.0034724. PMID:22496848

Hyatt AJ, Rajan MS, Burling K, Ellington MJ, Tassoni A, Martin KR. Release of vancomycin and gentamicin from a contact lens versus a fibrin coating applied to a contact lens. Invest Ophthalmol Vis Sci. 2012 Mar 9. [Epub ahead of print] PMID: 22408014

Afshari F, Jacobs C, Fawcett JW and Martin KR. Wet Age Related Macular Degeneration in “Age Related Macular Degeneration – The Recent Advances in Basic Research and Clinical Care” Ed: Gui-Shuang Ying, Publisher: InTech, January 2012. ISBN 978-953-307-864-9

Landers J, Martin K, Sarkies N, Bourne R, Watson P. A Twenty-Year Follow-up Study of Trabeculectomy: Risk Factors and Outcomes. Ophthalmology 2012 Apr;119(4):694-702. Epub 2011 Dec 23. PMID: 22196977

Jayaprakasam A, Martin KR, White AJ. A case of phacomorphic intermittent angle closure in a patient with retinopathy of prematurity and lenticular high myopia. Clin Experiment Ophthalmol. 2011 Dec 15. doi: 10.1111/j.1442-9071.2011.02743.x. [Epub ahead of print] PMID: 22171987

Lorber B, Guidi A, Fawcett JW, Martin KR. Activated retinal glia mediated axon regeneration in experimental glaucoma. Neurobiol Dis. 2012 Jan;45(1):243-52. Epub 2011 Aug 10. PMID: 21867754

Limb GA, Martin KR; the Sixth ARVO/Pfizer Ophthalmics Research Institute Conference Working Group. Current Prospects in Optic Nerve Protection and Regeneration: Sixth ARVO/Pfizer Ophthalmics Research Institute Conference. Invest Ophthalmol Vis Sci. 2011 Jul 29;52(8):5941-5954. PMID: 21804096

Johnson TV, Bull ND, Martin KR. Stem cell therapy for glaucoma: possibilities and practicalities. Expert Rev Ophthalmol. 2011 Apr 1;6(2):165-174. PMID: 21686079

Bull ND, Martin KR. Toward stem cell-based therapies for retinal neurodegenerative diseases. Stem Cells. 2011 Aug;29(8):1170-5. PMID: 21674700

Johnson TV, Martin KR. Broadening our focus in the search for cell transplantation-based glaucoma therapies. Eye 2011 May;25(5):541-3. PMID: 21562584

van Oterendorp C, Diaz-Santana L, Bull N, Biermann J, Jordan JF, Lagrèze WA, Martin KR. Light scattering and wavefront aberrations in in vivo imaging of the rat eye: a comparison study. Invest Ophthalmol Vis Sci. 2011 Jun 28;52(7):4551-9. PMID: 21546535

Bull ND, Johnson TV, Welsapar G, Dekorver NW, Tomarev SI, Martin KR. Use of an adult retinal explant model for screening of potential retinal ganglion cell neuroprotective therapies. Invest Ophthalmol Vis Sci 2011 May 17;52(6):3309-20. PMID: 21345987

Johnson TV, Bull ND, Martin KR. Neurotrophic Factor Delivery as a Protective Treatment for Glaucoma. Exp Eye Res 2011;93:196-203. PMID: 20685205

van Oterendorp C, Lorber B, Jovanovic Z, Yeo G, Lagrèze WA, Martin KR. Exp Eye Res 2011 Feb;92(2):138-46. Epub 2010 Dec 7. The expression of dynein light chain DYNLL1 (LC8-1) is persistently downregulated in glaucomatous rat retinal ganglion cells. PMID: 21145319

Avadhanam VS, Khaw PT, Martin KR. Long-Term Ocular Follow-up in a Case With Hereditary Mucoepithelial Dysplasia. J Pediatric Ophthalmology and Stabismus 2010 Nov 23;47:e1-4. doi: 10.3928/01913913-20101118-02. PMID: 21117525

Noack C, Martin KR, Diaz-Santana L. An ex vivo rat eye model to aid development of high-resolution retina imaging devices for rodents. J Modern Optics 2010; 57(16): 1555-1563

Marina N and Martin KR. A semi-automated targeted sampling method to assess optic nerve axonal loss in a rat model of glaucoma. Nature Protocols 2010;5(10):1642-1651

Hyatt A, Wang D, Kwok JC, Fawcett JW, Martin KR. Controlled release of chondroitinase ABC from fibrin gel reduces the level of inhibitory glycosaminoglycan chains in lesioned spinal cord. J Controlled Release 2010 Oct 1;147(1):24-9. Epub 2010 Jul 8.

Martin KR. Progression under the microscope: can basic science provide the link between structural and functional deterioration? Eur Ophthalmic Rev 2010; 3(2):27-29.

Afshari FT, Kwok JC, Andrews MR, Blits B, Martin KR, Faissner A, Ffrench-Constant C, Fawcett JW. Integrin activation and integrin alpha9 expression enhance retinal pigment cell adhesion and migration on normal and AMD-damaged Bruch’s membrane. Brain. 2010 Feb;133(Pt 2):448-64. PMID: 20159768

Johnson TV, Bull ND, Tomarev SI, Hunt DP, Martin KR. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma.. Invest Ophthalmol Vis Sci.  2010 Apr;51(4):2051-9. PMID: 19933193

Johnson TV, Bull ND, Martin KR. Identification of barriers to retinal engraftment of transplanted stem cells. Invest Ophthalmol Vis Sci 2010 Feb;51(2):960-70. PMID: 19850833

Bull ND and Martin KR. Using stem cells to mend the retina in ocular disease. Regenerative Medicine 2009 Nov;4(6):855-64. PMID: 19903004

Bull ND, Irvine K-A, Franklin RJ,  Martin KR. Transplanted oligodendrocyte precursor cells reduce neurodegeneration in a model of glaucoma. Invest Ophthalmol Vis Sci. 2009;50(9):4244-5. PMID: 19357352

Gasparini L, Crowther RA, Martin KR, Berg N, Coleman M, Goedert M, Spillantini MG. Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: effects on axonal viability. Neurobiol Aging. 2009 Apr 6. [Epub ahead of print] PMID: 19356824

Johnson TV, Bull ND, Martin KR. Transplantation prospects for the inner retina. Eye 2008 Dec 19. [Epub ahead of print] PMID: 19098702

Bull ND, Johnson TV, Martin KR. Stem cells for neuroprotection in glaucoma. Prog Brain Res. 2008;173:511-9. PMID: 1892913

Beirowski B, Babetto E, Coleman MP, Martin KR. The Wlds gene delays axonal but not somatic degeneration in a rat glaucoma model. Eur J Neurosci 2008;28:1166–1179. PMID: 18783366

Martin KR. “Stem cells in glaucoma” in “Glaucoma” (First Edition), edited by Tarek Shaarawy, Mark B Sherwood, Roger Hitchings and Jonathan G. Crowston, Elsevier, 2008

Bull ND, Limb GA and Martin KR. Human Müller stem cell (MIO-M1) transplantation in a rat model of glaucoma: survival, differentiation and integration. Invest Ophthalmol Vis Sci. 2008;49(8):3449-56. PMID: 18408183

Johnson TV and Martin KR. Development and characterization of an adult retinal explant organotypic tissue culture system as an in vitro intraocular stem cell transplantation model. Invest Ophthalmol Vis Sci 2008;49(8):3503-12. PMID: 18408186

Agrawal P and Martin KR.  Ciliary body position variability in glaucoma patients assessed by scleral transillumination. Eye 2008;22(12):1499-503. PMID: 18356924

Bull ND and Martin KR. Optic nerve restoration: new perspectives. J Glaucoma 2007 16(5):506-11.  PMID: 17700293

Martin KR, Quigley HA, Valenta DF, Kielczewski J, Pease ME. Optic nerve dynein motor protein distribution changes with intraocular pressure elevation in a rat model of glaucoma. Exp Eye Res 2006;83(2):255-62. PMID: 16546168

Levkovitch-Verbin H, Quigley HA, Martin KR, Harizman N, Valenta DF, Pease ME, Melamed S. The transcription factor c-jun is activated in retinal ganglion cells in experimental rat glaucoma. Exp Eye Res. 2005;80(5):663-70.

Martin KR and Quigley HA. Gene therapy for optic nerve diseases. Eye 2004;18:1049-1055.

Martin KR, Quigley HA, Zack DJ, Klein RL, Levkovitch-Verbin H, Valenta D, Baumrind LA, Pease ME, Hauswirth WW. Gene therapy with brain derived neurotrophic factor as a protection for retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci  2003;43:2236-2243

Levkovitch-Verbin H, Quigley HA, Martin KR, Zack D, Pease ME, Valenta D model to study differences between primary and secondary degeneration of retinal  ganglion cells in rats by partial optic nerve transection. Invest Ophthalmol Vis Sci 2003;44(8):3388-93

Martin KR, Levkovitch-Verbin H, Valenta D, Baumrind LA, Pease ME, Quigley HA. Retinal glutamate transporter changes in experimental glaucoma and following optic nerve transection in the rat.  Invest Ophthalmol Vis Sci 2002;43(7):2236-43.

Martin KR and Quigley HA. Gene delivery to the eye using adeno-associated virus vectors. Methods 2002;28(2):267-75

Levkovitch-Verbin H, Martin KR, Quigley HA, Baumrind LA, Pease ME, Valenta D. Measurement of amino acid levels in the vitreous humor of rats after chronic intraocular pressure elevation or optic nerve transection.   J Glaucoma. 2002;11(5):396-405.

Levkovitch-Verbin H, Quigley HA, Martin KR, Valenta D, Baumrind LA, Pease ME. Translimbal laser photocoagulation to the trabecular meshwork as a model of glaucoma in rats. Invest Ophthalmol Vis Sci. 2002;43(2):402-10.

 

<< Back to Principal investigators