Qualifying mouse models of spontaneous, progressive age-related macular degeneration

Age-related macular degeneration (AMD) is a chronic disease of the retina, which results in the loss of central vision and is the main cause of blindness in the Western World in people over 55 years age. More than 30 million people in the developed world suffer from AMD and with increasing life expectancy and changing environmental factors the incidence of AMD continues to increase. Though several treatments for AMD exist, they target ~ 20% of patients with the disease and are effective at restoring vision to a minority of those treated. Those with visual impairment or blindness have a significant impairment in quality of life and functional independence and are a considerable burden on healthcare resources. Recent scientific studies have led to the discovery of several genes linked to inflammation and the immune system, termed the complement pathway, that appear to play a major role in the onset and progression of AMD. However, there are many different abnormalities associated with AMD, including alterations to the neurons and support tissues of the retina, improper removal of waste products and in the most severe stage, growth of chaotic and sight-threatening blood vessels and oedema. Researchers are now focused on determining which of these abnormalities are caused by the complement pathway, and therefore could be targeted by new medicines that are now being developed by pharmaceutical companies. Animal models that mimic human AMD are urgently needed to begin testing these new potential medicines. By identifying animal models that accurately reflect the abnormalities observed in AMD, we hope to test the new therapies and identify at which stage of the disease, and for which abnormalities we should focus on in human clinical trials. We propose to work in partnership with a pharmaceutical company named Jerini Ophthalmic to evaluate two mouse models of AMD, compare them to the human condition, and use the models to test an inhibitor of the complement pathway that Jerini Ophthalmic hopes to test in human clinical trials within the next 1-2 years.

Age-Related Macular Degeneration (AMD) is a chronic, progressive disease of the central retina, called the macula, which results in the loss of central vision. It is the leading cause of severe vision loss and blindness in patients over the age of fifty in the developed world. A major breakthrough in AMD research occurred following recent publication of several human genetic studies linking 3 different gene loci encoding components of the complement pathway to AMD. These data implicate the complement cascade as the first molecular pathway to target in therapeutic strategies aimed at the prevention of advanced AMD. This new therapeutic approach will hopefully improve the outcomes for the large majority of AMD patients who have no treatment options (i.e. geographic atrophy) or who do not respond to current ?wet? AMD treatments targeting Vascular Endothelial Growth Factor (VEGF). Remarkably, several complement cascade antagonists are already in early clinical testing or late-stage pre-clinical development. Yet, despite having a highly validated biological pathway to target, and several potential antagonists in drug development, the pathogenic mechanisms by which the complement cascade triggers progression from early stages of AMD to either of the sight-threatening forms, geographic atrophy or choroidal neovascularisation, are ill-understood. Clarity around at which stage of AMD progression complement-induced dysfunctions play a role will be critical for designing effective clinical trials to test this promising area of disease prevention. Progress in meeting the challenges outlined above is hampered by the lack of qualified, validated animal models that enable credible comparative studies to pinpoint a therapeutic window for the application of complement antagonists in clinical trials. In collaboration with Jerini Ophthalmic, a small ophthalmic biotech, we propose to evaluate and qualify the suitability of two mouse genetic models which together appear to recapitulate most of the pathologies associated with the progression of AMD, and to determine the comparative efficacy of VEGF and complement antagonism on disease progression.