Macular Degeneration Research
Peter Humphries, Ph.D.
Trinity College Dublin
Title: The Inflammasome and Novel Therapeutic Targets in AMD
Non-Technical Title: Inflammation and AMD
Matthew Campbell, B.Sc. (Hons), Ph.D.
Trinity College Dublin
Duration: July 1, 2011 - June 30, 2013
Award Type: Standard
Award Amount: $100,000
Our proposed research will aim to identify and implicate a novel inflammatory pathway in the progression of AMD. This pathway is termed the "inflammasome" and the identification of novel therapeutic targets for AMD could pave the way for more robust and reliable therapies for both dry and wet AMD. Indeed, if the inflammasome were to be implicated in the development of AMD, the targets for potential therapies would be greatly improved. Moreover, low molecular weight inhibitors or indeed augmenters of inflammasome component activation could also be investigated for therapeutic use.
The body's immune system can ward off attacks by bacteria, viruses and other external threats. However, it also has systems in place to respond to internal threats, like the build-up of drusen—tiny waste deposits in the back of the eye—that happens in age-related macular degeneration (AMD). In previous studies, Drs. Peter Humphries, Matthew Campbell, and colleagues have observed that drusen can trigger a localized immune response by a collection of proteins called the "inflammasome." In this project, they will determine why this occurs and what components of the inflammasome play key roles in causing AMD. This group will also screen a range of drugs that could tip the protein composition of drusen to a healthy ratio to better-treat AMD. Many of the drugs they will use in the screen already have regulatory approval for human use, which may accelerate their entry into human clinical trials.
Doyle*, SL, *Campbell, M, , Ozaki, E, Salomon, RG, Mori, A, Kenna, PF, Kiang, AS, Humphries, MM, Lavelle, EC, O'Neill, LAJ, Hollyfield, JG, and Humphries, P. NLRP3 plays a protective role during the development of age related macular degeneration through the induction of IL-18 by drusen components. Nature Medicine (2012) Apr 8
Typically, inflammatory responses in the human body are caused as a result of bacterial or viral infection. However, in chronic conditions like AMD, a form of "sterile" inflammation has recently been described whereby localized immune responses can occur in distinct organs and tissues of the body. This localized response culminates in the activation of a protein complex termed the "inflammasome" which mediates the secretion of two highly inflammatory cytokine proteins, called IL-1beta and IL-18.
Dr. Humphries’ and Dr. Campbell’s team has recently discovered that a component of the inflammasome, IL-18, appears to play a protective role in the development of wet AMD by preventing the expression of VEGF, a key protein involved in the development of choroidal neovascularization (CNV; the damaging ingrowth of blood vessels into the retina). The team discovered that mice lacking the component IL-18 developed exacerbated CNV, which directly implies that this molecule is central to the development of the disease. Current antibody-based therapies in use for treating wet AMD involve the direct intraocular injection of medication targeting VEGF. The team has discovered that IL-18 can actually decrease VEGF levels itself which, while leading to a better understanding of the disease process, could also lead to a new therapeutic strategy for wet AMD. In the future, drugs directed against the inflammasome, including IL-18, will be tested to see if they can reduce the drusen deposits in the retina.