TLR2 As A Novel Therapeutic Target For CNV Pathogenesis
Although current therapies for choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) are effective in the short term, they have some disadvantages. Current therapies are expensive, they address the symptoms rather than the cause of the disease, and concerns have been raised about their long-term efficacy and safety. The objective of this proposal is to validate the functional role of toll-like receptors (TLRs), a component of the innate immune system, in CNV pathogenesis, and to evaluate TLRs as a novel, effective and safe therapeutic target for the treatment of CNV.
Choroidal neovascularization (CNV), which involves the creation of abnormal blood vessels, accounts for approximately 80 percent of severe vision loss associated with the wet form of AMD (called that because CNV causes fluid or blood to leak into the central region of the retina, called the macula, which damages vision). Current treatment using anti-vascular endothelial growth factor (VEGF) therapy, in other words, stopping a protein that promotes new growth of blood vessels, can be an effective treatment for CNV, but its long-term benefit is questionable, and potential retinal side effects are emerging. Importantly, patients require lifelong treatment, since anti-VEGF therapies only temporarily suppresses the symptoms caused by CNV, and are largely ineffective against the underlying cause.
A more effective therapy that targets the root cause of CNV should constitute the next generation of treatment. There is strong support for the idea that abnormal inflammation, mediated in part by the innate immune system, plays a critical role in the development of AMD. Dr. Ng and his team hypothesized that the toll-like receptors (TLRs), which are components of innate immunity and responsible for regulating inflammatory responses at the molecular levels, could contribute to the development of CNV. By using animal models, the team will determine if the TLRs are successful therapeutic targets for CNV.
Details. Dr. Ng and his team have generated preliminary data providing strong evidence for a role of TLRs in the pathogenesis (in disease) of CNV. Blocking a specific TLR in the eye suppressed CNV, with therapeutic success comparable to that of anti-VEGF in an animal model. Furthermore, inhibiting this specific TLR dramatically reduced inflammation in the eye. This suggests that the therapeutic effect of TLR inhibition is moderated at least partly by anti-inflammation.
Based on these observations, the team hypothesizes that long-term uncontrolled activation of TLRs in the eye, likely by toxic end products of lipids oxidation, triggers a localized inflammatory reaction. This abnormal, localized inflammatory response eventually leads to tissue damage at the back of the eye, and to the growth of new blood vessels as an adaptive response to tissue injury.
In order to test the hypothesis that TLRs play a role in CNV development and to validate TLRs as novel therapeutic targets for CNV pathogenesis, Dr. Ng and his team will perform the following studies with the generous support of the BrightFocus Foundation. First, the contribution to CNV pathogenesis by various TLRs-expressing tissues in the back of the eye will be determined in an animal model. Second, therapeutic effects of highly selective pharmacological TLRs pathway inhibitors in CNV development will be determined. Third, to validate TLRs as therapeutic targets for human CNV, their expression will be examined in clinical samples. Finally, to begin to translate these results to human disease, the team will examine the effect of TLR inhibition on suppressing the degeneration of human cells isolated from the eye by toxic end products of lipid oxidation. The results from this project will provide important mechanistic data about the contribution of TLRs on CNV pathogenesis, and potentially set forth an effective strategy for targeting this pathway with treatments that address the underlying cause of wet AMD and help prevent vision loss.
About the Researcher
Eric Ng, PhD, currently is an assistant scientist at the Schepens Eye Research Institute and assistant professor in the Department of Ophthalmology at Harvard Medical School in Boston, MA. During his PhD training with Patricia D’Amore, PhD, at the Schepens Eye Research Institute and Harvard Medical School, Eric began his study on the complex biology of vascular endothelial growth factor (VEGF) in both normal development and in diseases. The current research aim for the Ng laboratory is to develop a program of biomedical research that will help refine our current use of anti-VEGF therapeutics and define new targets for developing the next generation of pharmacotherapies. Current research projects in the Ng lab include investigating the neuroprotective function of VEGF in various retinopathies and in glaucoma; identifying novel targets for anti-angiogenesis and anti-inflammation in neovascular AMD, diabetic retinopathy and retinopathy of prematurity; and, characterizing a novel anti-inflammatory strategy for ocular disease. In addition to this research grant from the BrightFocus Foundation, the Ng’s lab is supported by funding from the Curing Kids Fund and the Grimshaw Foundation. Previous research supports for Dr. Ng include the Medical Research Council project grant, UCL Impact Studentship, and Diabetes UK research grant.
"When I was a child, I was ill and often visited the doctor. It was during this time that I became fascinated by how drugs, these small white pills, could make me feel better so quickly. My interest in drug research grew during graduate school as I learned more about how drugs work. I was particularly excited by the new class of molecular therapeutics being developed, which had been based on disease mechanism research and rational drug design. Because I had studied the biology of vascular endothelial growth factor (VEGF), I had the opportunity to be involved in the development of the first anti-VEGF therapeutic agent for age-related macular degeneration (AMD) at Eyetech Pharmaceuticals soon after my graduate school training. Being able to witness how this drug was helping patients with blinding eye diseases and, at the same time, applying my knowledge of basic biomedical research for drug discovery and development, validated my passion for translational vision research.
My personal goal is to continue my study of basic disease mechanisms for AMD and other blinding ocular diseases, and to develop new and better therapeutic approaches. This current project, in which we hope to validating toll-like receptors as a novel target for treating wet AMD, is indeed part of a program of research that I hope to develop to improve on current anti-VEGF therapies. Only with the generous support of the BrightFocus Foundation are we able to continue this worthy project. I strongly believe that our findings will contribute directly and/or indirectly to development of the next generation of therapy for wet AMD."
First published on: July 15, 2015
Last modified on: July 1, 2017