AMD Breakthrough

[caption id='attachment_964' align='alignright' width='400' caption='Experiments in mouse models suggest a direct causal link between oxidative stress and AMD pathology. CFH polymorphisms may alter the ability to bind MDA, a by-product of oxidative stress, representing a major advance in our understanding of AMD pathology'][/caption]

An Austrian research team has achieved a major breakthrough in the understanding of how certain alleles of complement factor H (CFH) increase the risk of age-related macular degeneration (AMD).

The report on the research team’s findings, published in the journal Nature, fills in a considerable part of the CFH story originally discovered by a number of research groups in 2005.

The new research identifies malondialdehyde (MDA) – a decomposition product of lipid peroxidation – as a ligand of CFH which may now explain how the original risk association operates at a molecular level. More critically, the new research shows how normal CFH may prevent MDA-mediated inflammation in RPE and macrophage cells giving rise to opportunities for therapeutic intervention.

As ophthalmologists well know, AMD may be divided into a non-exudative 'dry' form and an exudative 'wet' form. The dry form, which accounts for 85 per cent of cases, involves fatty deposits, known as drusen, which build up over time behind the retina. The wet form, which accounts for the remaining 15 per cent of cases, involves the growth of abnormal blood vessels (neovascularisation) and leakage of blood and other fluid from behind the retina.

Many of the recent therapeutic approaches to tackle AMD have focused on a key target of the neovascularisation process – a molecule known as VEGF (vascular endothelial growth factor) which can promote new blood vessel growth. Wet macular degeneration usually begins as the dry form.

Following a series of independent research papers in late 2005 suggesting a link between the body’s immune system and AMD, further investigations established the alternative complement system as a potentially critical player that may help scientists to join the dots between drusen and the symptomatic degeneration of the macula.

Understanding the links between the genetic susceptibility data and the clinical symptoms should provide a framework for a deeper understanding of AMD pathogenesis and consequently contribute to identifying new therapeutic targets to slow or halt vision loss associated with the disease.

Genetic studies

A series of genetic studies conducted since 2005 have shown that CFH was a clear smoking gun behind much of AMD, but how it was operating remained a mystery.

One of the first CFH reports, by Dr Robert Klein, of Rockefeller University, in New York, found that individuals with a CFH variant that substitutes a tyrosine amino acid for a histidine at position 402 increased the likelihood of developing AMD 4.6-fold if present on one allele and 7.4-fold if present on both alleles.

A second CFH paper, by Dr Albert Edwards, now affiliated with the Institute for Retina Research in Dallas, Texas, reported that “possession of at least one histidine at amino acid 402 (of the CFH gene) increased the risk of AMD 2.7-fold and accounts for 50 per cent of the attributable risk of AMD.†A further CFH study found that the CFH haplotype significantly increased the risk for AMD and that a common variant likely explains approximately 43 per cent of AMD in older adults.

The physical link between CFH that operates within the alternative complement system and AMD can be found in the drusen or extra-cellular deposits found in patients with AMD. Several components of the complement cascade have been found in drusen deposits and have led to the hypothesis that AMD may result from dysfunctional inflammation which incorporates inappropriate complement activation.

The complement cascade is an innate part of the immune defence system, consisting of over 30 serum proteins. In general, substances on the surface of microbes can trigger the complement cascade, which activates a series of biochemical steps leading to the lysis (or bursting) of invading cells. However, certain complement proteins may also help trigger inflammation.

CFH genetic alterations This most recent Austrian research – by Mr David Weismann, Dr Christoph Binder and research colleagues at the Centre for Molecular Medicine of the Austrian Academy of Sciences – appears to explain how the CFH genetic alterations might mediate their effect. Results from animal models lacking immunoglobulins showed that over 55 per cent of peptides bound to malondialdehyde (MDA) could be attributed to CFH.

Mapping of the binding site for MDA on CFH showed that it crossed the amino acid position 402, highlighted in the original genetic association studies and, most importantly, the H402 variant of CFH showed reduced MDA binding by up to 23 per cent in the plasma of heterozygotes and up to 52 per cent in homozygotes. Normal CFH then appears to protect against inflammation by inhibiting the complement pathway, however once mutated, the ability for CFH to control the inflammation associated with AMD appears to be lost.

The MDAs are created through the action of oxygen radicals and are a normal decomposition product of lipid peroxidation. When the MDAs react with normal cell proteins, they form adducts that act as biomarkers of oxidative stress inducing inflammation in a variety of conditions ranging from atherosclerosis to AMD. The major finding from the study appear to suggest that functioning CFH is able to suppress this inflammatory response by mopping up the MDA adducts. A clear implication here is that targeting of the MDA adducts may now open a new therapeutic strategy for the treatment of AMD, and possibly other chronic degenerative disorders.

“Undoubtedly, there are multiple defences against the ubiquitous MDA adducts,†the researchers concluded. “The described homeostatic response may be particularly limiting in the eye, as opposed to other sites where MDA adducts accumulate such as the vascular wall. The findings described here may lead to novel approaches exploiting endogenous defence mechanisms for the prevention and therapy of chronic inflammation in general.â€