Keith Martin
Professor of Ophthalmology, University of Cambridge
Honorary Consultant Ophthalmic Surgeon, Addenbrooke’s Hospital, Cambridge
Research Group
Post-doctoral scientists:
- Dr Natalie Bull, PhD (Senior Post Doc)
- Dr Barbara Lorber, PhD
- Dr Andrew White, MD PhD (2010-)
- Dr Christian Noack, MD PhD (2006-8)
- Dr Sarah Hughes, PhD (2005-6)
- Dr Nephtali Marina Gonzalez, MD PhD (2007-8)
PhD students:
- Alessia Tasoni (2010 -)
- Janosch Heller (co-supervisor 2009 -)
- Alex Hyatt (2007- )
- Thomas V Johnson (2006-2010)
- Bogdan Beirowski (co-supervisor 2006-8)
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 Luis Diaz-Santana, City University, London (adaptive optics imaging systems)
- Dr Astrid Limb and Professor Peng Khaw, Institute of Ophthalmology, London (supply of Müller stem cell lines)
- Professor Harry A Quigley, Wilmer Eye Institute, the Johns Hopkins University, Baltimore, USA (Quantification of optic nerve damage in glaucoma)
- Dr Mike Modo, Kings College, London (MRI imaging of paramagnetic nanobeads)
- Dr Giampietro Schiavo, London Research Institute (manufacture and supply of paramagnetic tracers)
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 / Pfizer Ophthalmics / Carl Camras Translational Research Award for 2010 and the National Centre for the Refinement, Replacement and Reduction of Animals in Research Prize 2009.
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.
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 paramagnetic nanoparticles traced by high resolution magnetic resonance imaging and adaptive optics imaging systems to allow the ultrastructure of individual cells to be visualised in the living retina. 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 gene therapy approaches to 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. In current work we are investigating the potential neuroprotective effects of gene therapy with other neurotrophic factors in 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, currently a post doc in the lab, 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.