A new approach to therapy for a common cause of blindness
- Type of funding: Clinical Fellowship
- Grant Holder: Mr Tiarnan Keenan
- Institute: University of Manchester
- Region: North West
- Start date: October 2010
- End Date: September 2013
- Eye Category: AMD
Age-related macular degeneration is one of the world’s most common causes of blindness in older people. At the moment, there aren’t any treatments that can give people their central vision back once it has gone.
The risk of getting AMD partly depends on which genes you have. About 1 in 3 people with European ancestors have inherited a version of the gene ‘complement factor H’ that makes AND more likely.
Complement factor H usually protects us from tissue damage by our own immune system. But the type linked to AMD can’t bind together with certain parts of the macula (the central part of the light-sensitive layer of the eye) well enough to do the job.
The aim of this project is to develop treatments that make it easier for complement factor H to bind to the macula. There are several ways it could be done so the team is comparing them. Ultimately they want to develop a treatment that prevents AMD from developing.
Complement Factor H – towards novel therapeutics for age-related macular degeneration
The common Y402H polymorphism in the complement factor H (CFH) gene is a major risk factor for age-related macular degeneration (AMD). CFH is a plasma protein that protects host tissues against complement-mediated damage by binding polyanions on tissue surfaces and locally inhibiting the alternative complement pathway. Recent research from the sponsoring laboratories has demonstrated that the two forms of CFH (402H and 402Y) exhibit significantly different binding specificities for sulphated glycosaminoglycans (GAGs), and that the 402H (disease-associated) variant binds significantly less well to sulphated GAGs in human Bruch’s membrane.
The lower level of CFH bound to Bruch’s membrane in individuals carrying the 402H allele is likely to make a major contribution to the initiation and development of AMD, through local dysregulation of the complement pathway. Increased complement turnover at Bruch’s membrane would lead to chronic inflammation at the RPE/choroid interface, which is a major feature of the pathophysiology of AMD.
The team hypothesise that enhancing the level of binding of the 402H form of CFH to Bruch’s membrane may be used as a preventative treatment for AMD. The initial aim of this project is to determine in vitro whether the binding of the 402H form of CFH to Bruch’s membrane proteoglycans can be enhanced by increasing GAG sulphation. Once achieved then in vivo experiments will be performed to determine whether the GAGs in Bruch’s membrane can be modified using a gene therapy approach, and whether this enhances the binding of the 402H form of CFH to Bruch’s membrane.
The research team found a link between complement factor H and a substance called ‘heparan sulphate’ that’s found in the eye. They discovered that the amount of heparan sulphate in the eye goes down as we get older. This makes it harder for complement factor H to protect the eye from damage. It explains why some people are more at risk of AMD than others as they age. It also suggests heparan sulphate as a new target for future treatments.
- Keenan TDL, Toso M, Pappas C, Nichols L, Bishop PN, Hageman GS. Assessment of Proteins Associated With Complement Activation and Inflammation in Maculae of Human Donors Homozygous Risk at Chromosome 1 CFH-to-F13B. Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4870–9.
- Keenan TDL, Pickford CE, Holley RJ, Clark SJ, Lin W, Dowsey AW, et al. Age-Dependent Changes in Heparan Sulfate in Human Bruch’s Membrane: Implications for Age-Related Macular Degeneration. Investigative Opthalmology & Visual Science [Internet]. 2014 Aug 26 55(8):5370.
- Clark SJ, Keenan TDL, Fielder HL, Collinson LJ, Holley RJ, Merry CLR, et al. Mapping the Differential Distribution of Glycosaminoglycans in the Adult Human Retina, Choroid, and Sclera. Investigative Opthalmology & Visual Science [Internet]. 2011 Aug 17 ;52(9):6511.
- Keenan TDL, Clark SJ, Unwin RD, Ridge LA, Day AJ, Bishop PN. Mapping the Differential Distribution of Proteoglycan Core Proteins in the Adult Human Retina, Choroid, and Sclera. Invest Ophthalmol Vis Sci [Internet]. 2012 Nov ;53(12):7528–38.
- Langford-Smith A, Keenan TDL, Clark SJ, Bishop PN, Day AJ. The Role of Complement in Age-Related Macular Degeneration: Heparan Sulphate, a ZIP Code for Complement Factor H? J Innate Immun [Internet]. 2014 Jun ;6(4):407–16.