A Potential Intravenous Treatment for Wet Age-Related Macular Degeneration: Interleukin-18

Translational Medicine logo

A research group, composed of members from the Republic of Ireland, the United Kingdom, and the United States, has determined that a protein called interleukin-18 (IL-18), which is a component of the immune system linked to inflammatory disorders, has the ability to suppress production of the harmful bleeding/leaking blood vessels that characterize wet age-related macular degeneration (AMD).

In addition, the researchers have demonstrated that IL-18 can be administered intravenously, which, if proven successful in human clinical trials, could offer advantages over the current treatment model, which requires injection of Lucentis, Avastin, or Eylea directly into the eye.

Please note: This “proof-of-concept” research is in its earliest stages and has been conducted only in pre-clinical settings with laboratory mice. Nevertheless, the concept shows promise for persons with wet AMD.


The research, entitled IL-18 Attenuates [i.e., weakens or reduces] Experimental Choroidal Neovascularization as a Potential Therapy for Wet Age-Related Macular Degeneration (explained below), was published in the April 2, 2014 issue of Science Translational Medicine.

Science Translational Medicine is an interdisciplinary medical journal, established in October 2009 by the American Association for the Advancement of Science, that covers basic, translational, and clinical research on human diseases. Translational research helps to make findings from basic science useful for practical applications that enhance human health and well-being.

The authors are Sarah L. Doyle, Ema Ozaki, Kiva Brennan, Marian M. Humphries, Kelly Mulfaul, James Keaney, Paul F. Kenna, Arvydas Maminishkis, Anna-Sophia Kiang, Sean P. Saunders, Emily Hams, Ed C. Lavelle, Clair Gardiner, Padraic G. Fallon, Peter Adamson, Peter Humphries, and Matthew Campbell, who represent the following institutions: Trinity College Dublin, Ireland; Our Lady’s Children’s Hospital, Dublin; Royal Victoria Eye and Ear Hospital, Dublin; National Eye Institute, Bethesda, Maryland; and GlaxoSmithKline, UK.

Wet Macular Degeneration

In wet, or exudative, macular degeneration (AMD), the choroid (a part of the eye containing blood vessels that nourish the retina) begins to sprout abnormal blood vessels that develop into a cluster under the macula (called choroidal neovascularization).

The macula is the part of the retina that provides the clearest central vision. Because these new blood vessels are abnormal, they tend to break, bleed, and leak fluid under the macula, causing it to lift up and pull away from its base. This damages the fragile photoreceptor cells, which sense and receive light, resulting in a rapid and severe loss of central vision.

Current Treatments for Wet Macular Degeneration

Angiogenesis is a term used to describe the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. Sometimes, however, excessive and abnormal blood vessel development can occur in diseases such as cancer (tumor growth) and AMD (retinal and macular bleeding).

Substances that stop the growth of these excessive blood vessels are called anti-angiogenic (anti=against; angio=vessel; genic=development), and anti-neovascular (anti=against; neo=new; vascular=blood vessels).

The focus of current treatments for wet AMD is to reduce the level of a particular protein (vascular endothelial growth factor, or VEGF) that stimulates abnormal blood vessel growth in the retina and macula; thus, these drugs are classified as anti-VEGF treatments. At present, these drugs (Lucentis, Avastin and Eylea) are administered by injection directly into the eye after the surface has been numbed.

In the case of this particular research, the study team has determined that IL-18 also inhibits VEGF production.

More about the Study

From Scientists make major breakthrough in age-related macular degeneration therapy in Medical Xpress News:

The scientists found that a component of the immune system, IL-18, acts as a guardian of eyesight by suppressing the production of damaging blood vessels behind the retina at the back of the eye. In addition, in pre-clinical models, it was shown that IL-18 can be administered in a non-invasive way, which could represent a major improvement on the current therapeutic options that are open to patients.

“We were initially concerned that IL-18 might cause damage to the sensitive cells of the retina, because it is typically linked to inflammation. But surprisingly we found that low doses had no adverse effects on the retina and yet still suppressed abnormal blood vessel growth,” said Assistant Professor in Immunology at Trinity, Sarah Doyle.

Treatment options for wet AMD are currently limited to the end stages of the disease. Regular injections of antibodies must be made directly into the eye to mop up a problematic molecule termed VEGF. However, the Trinity scientists found that IL-18 directly inhibits VEGF production, and that it can work as effectively as the current treatment when administered via a non-invasive intravenous injection in pre-clinical settings.

From Science Translational Medicine

From the article abstract:

Age-related macular degeneration (AMD) is the most common form of central retinal blindness globally. Distinct processes of the innate immune system, specifically activation of the NLRP3 inflammasome, have been shown to play a central role in the development of both “dry” and neovascular (“wet”) forms of the disease.

We show that the inflammatory cytokine interleukin-18 (IL-18) can regulate choroidal neovascularization formation in mice. We observed that … administration of … IL-18 has no effect on retinal pigment epithelial (RPE) cell viability, but that overexpression of pro–IL-18 or pro–IL-1ß alone can cause RPE cell swelling and subsequent atrophy, a process that can be inhibited by the promotion of autophagy.

[Editor’s note: Autophagy, a basic biological and metabolic process, “self-eats” cellular components that are unnecessary or dysfunctional to the cell, such as those that can cause the degenerative retinal changes that accompany AMD.]

A direct comparison of local and systemic administration of … IL-18 with current anti-VEGF (vascular endothelial growth factor)–based therapeutic strategies shows that IL-18 treatment works effectively alone and more effectively in combination with anti-VEGF therapy and represents a novel therapeutic strategy for the treatment of wet AMD.

VisionAware will provide updates of this research as it moves from the laboratory into human subject testing.

Additional Information