Breakthrough raises hope of preventing wet AMD

A new study led by Trinity College Dublin, in Ireland, finds that controlling or raising levels of the immune system component IL-18 in the retinas of patients with dry age-related macular degeneration (AMD), could prevent it progressing into the wet form of the disease. The researchers write about their findings in the 8 April online issue of Nature Medicine. AMD is the leading cause of central vision loss worldwide. Its advanced form makes every day life very difficult, preventing people from doing what many take for granted, such as read the paper, watch television, drive, use a computer, and see expressions on the faces of people they are in conversation with. A characteristic hallmark of AMD is having too many "drusen": yellowish-white deposits in the macula, the central region of the retina. These are usually diagnosed in an eye exam. There are two forms of AMD: dry and wet. Dry AMD is the more common. It develops very slowly over a number of years, during which there is a gradual change in central vision. A small minority of people with dry AMD go on to develop wet AMD, which develops quickly, with serious loss of central vision occuring over a short period of time. In wet AMD, the cells of the macula degenerate, causing growth of underlying new blood vessels to compensate, but these result in damage and scarring of the macula. There are currently no treatments for dry AMD apart from recommending lifestyle changes like giving up smoking, which is a known risk factor. Treatment is available for wet AMD, but it has to be given promptly, before the new blood vessels cause damage. The researchers write in their background information that although previous research has suggested activation of the immune system plays a role in the progression of AMD, we know little about the underlying biological mechanisms, such as the molecular pathways behind excessive drusen formation. Using drusens isolated from donor AMD eyes, together with clinical studies on mouse models of the disease, the researchers discovered certain molecular pathways containing an inflammasone protein called NLRP3, that when activated, lead to the secretion of two inflammatory components: IL-1beta and IL-18. NLRP3 protein is a member of a family of immune system proteins that help to start and regulate response to injury, toxins, or invasion by microorganisms. Co-author Dr Matthew Campbell, of Trinity College's Ocular Genetics Unit, told the press: "Traditionally, inflammation in the retina or indeed the eye in general is not beneficial and is a pathological hallmark of many eye diseases, including AMD. However we have identified, that one inflammatory component termed IL-18 acts as a so-called anti-angiogenic factor, preventing the progression of wet AMD." The researchers found that the progression from dry to wet AMD appears to be influenced by IL-18. They tested this on mice, using lasers to induce new blood vessels under the macular (laser-induced choroidal neovascularization or CNV). The induced vascularization was worse in mice lacking the NLRP3 protein, "directly implicating IL-18 in the regulation of CNV development", they write. "... our results directly suggest that controlling or indeed augmenting the levels of IL-18 in the retinas of patients with dry AMD could prevent the development of the wet form of disease, which leads us to an exciting new prospect for a novel therapy for AMD," said Dr Sarah Doyle, also from Trinity College's Ocular Genetics Unit. The research was carried out at Trinity College, in collaboration with the Cole Eye Institute at Cleveland, Ohio, in the US. Funds for the study came from Science Foundation Ireland, the American Health Assistance Foundation (AHAF), the Health Research Board (HRB) and Fighting Blindness Ireland.