New professorship in age-related macula...

Home » The Institute » News & Events » News » News Article

New professorship in age-related macula degeneration

Prof. Simon Clark started his work in Tuebingen at the Insitute for Ophthalmic Research.

Research work

My labs mission is to elucidate the mechanisms that drive age-related macular degeneration (AMD) with a motivation to identifying suitable therapeutic targets. In particular we focus on the role of the complement system, a powerful part of a host’s innate immune system, that is strongly linked through both genetics and biochemistry to modifying an individual’s risk of developing the disease. We are particularly interested in how the modulation of such an immune response can be harnessed to slow disease progression.

Genetic variants in genes encoding proteins of the complement system lead to a continuous, low-grade inflammatory response in the extracellular matrix (ECM) in the back of the eye. A major risk locus for AMD centres around the Regulators of Complement Activation (RCA) cluster on chromosome 1, which contains the CFH and CFHR1-5 genes. For years we have studied the biochemical and functional consequences of genetic variants in the CFH gene on its synthesised protein complement factor H (FH) and it’s splice variant factor H-like protein 1 (FHL-1). We have also been interested in understanding the role of Bruch’s membrane, its composition and diffusion properties, on maintaining immune homeostasis in the macula. Currently, our work focuses on a number of areas,

  1. The use of human eye tissue for understanding AMD: AMD is a peculiarly human disease, and our establishment of the Manchester Eye Tissue Repository (METR) in 2015, allowed us to make new discoveries through the use of phenotyped and genotyped human eye tissues that simply wouldn’t be possible using animal model systems. For example, we are currently defining an array of novel interactions we have identified between human primary RPE cells and their respective Bruch’s membrane enriched from the same donor eye.

  2. The role of the factor H-related proteins in AMD: The extended family of five FH related proteins (FHR1-5) share a very high degree of sequence homology with FH and are also genetically linked with risk of AMD. Not much is currently known about their function or role in mediating immune homeostasis in the retina. We are developing novel tools to allow the visualisation of each of these proteins in human macula tissue. Doing this in genotyped donor tissue will allow us to directly link FHR protein concentration and localisation with genetic risk, and allow us to identify binding partners for these understudied complement proteins.

  3. Patient diagnostics and stratification: It is becoming clear that AMD is an umbrella term that covers a range of diseases with similar end phenotype, but whose risk profile and developmental pathways are very different. We are developing analytical tools to measure specific blood borne markers in order to identify sub-populations of patients that will respond best to complement-mediated therapeutics.

  4. Therapeutic development: Ultimately, the reason to understand how AMD starts and progresses into vision loss is to identify a method of intervention. Our translational portfolio includes the development of novel complement modifiers that can be used as therapeutics in complement-mediated diseases of the eye, as well as around the body.

Personal background

Simon obtained his B.Sc. in Biochemistry (with Immunology) at the University of Aberdeen in 2002 and subsequently spent a year working in industry on the development of diagnostic tests for cardiovascular disease. In 2003 Simon matriculated at Oxford to begin his D.Phil. studies investigating the interaction of complement factor H (FH), an innate immune regulator, with endogenous sugar molecules as a mechanism for host recognition. It was during his time in Oxford where he was the first to describe the biochemical effects of a genetic polymorphism in FH associated with developing Age-related Macular Degeneration (AMD), the leading cause of blindness in the western World.

In 2006, Simon moved to the Faculty of Life Sciences, University of Manchester, to study further the regulation of innate immunity on extracellular matrices and successfully identified the sugar molecules that FH uses to anchor to Bruch’s membrane: heparan sulphate and dermatan sulphate. Structural studies subsequently identified that specific sulphation patterns of these sugars were being recognised by FH as a sort of binding ‘ZIP-code’ that dictated which extracellular matrix FH bound within the human body.

in 2013 Simon was awarded an MRC Career Development Fellowship and moved to the Faculty of Medicine and Human Sciences, University of Manchester. Simon used this opportunity to study potential roles of the factor H-related (FHR) proteins in the pathogenesis of AMD and other extracellular matrix diseases. Simon's work identified a protein, made by alternative splicing of the FH gene; called factor H-like protein 1 (FHL-1), is actually the main complement regulator in Bruch’s membrane. He also characterised the diffusion properties of human Bruch's membrane for soluble complement proteins. Both of these works fundamentally changed the way complement-mediated therapeutics were designed and delivered into the eye as treatments for retinal degenerative diseases. 

In 2015 Simon co-founded the Manchester Eye Tissue Repository (ETR) with Prof. Paul Bishop, where genotyped and phenotyped human eye tissue is collected and stored to act as an international resource for academic research into eye diseases: one of the only such resources in Europe and now houses ~1500 donors.

In 2019, Simon was honoured to accept the Helmut Ecker Endowed Professorship in AMD in the Institute for Ophthalmic Research, University of Tübingen. Today, Simon leads a research programme investigating the molecular mechanisms driving AMD, and the development of therapeutics to treat this devastating disease.