National Glaucoma Research
Paul A. Knepper, M.D., Ph.D.
University of Illinois at Chicago
Chicago, IL, United States
Title: Activation of Innate Immune Toll-4 Receptor in POAG
Non-Technical Title: Activation of Innate Immunity System and Gluacoma
Acknowledgements: Recipient of the Thomas R. Lee award for National Glaucoma Research
Duration: July 1, 2011 - June 30, 2014
Award Type: Standard
Award Amount: $100,000
We have identified a unified signaling pathway based on activation of innate immune system which results in an inflammatory cascade resulting in POAG. We have identified that cell trauma causes low-molecular-weight hyaluronic acid to start the pathway. Prevention of degradation of high-molecular-weight hyaluronic acid by potent hyaluronidase inhibitor could be novel therapy and the first therapy directly aimed at the cause of POAG.
Hyaluronic acid is a long-chain sugar polymer that is naturally present at high concentrations in the fluids of the eye and joints. Inflammation and cell damage in the eye will cut hyaluronic acid into smaller pieces (called low molecular weight hyaluronic acids which are pro-inflammatory) and this can tip the balance towards primary open-angle glaucoma (POAG). Dr. Knepper and colleagues will collect and test samples of the aqueous humor (found in the eye cavity in between the cornea and the lens) of people who are either healthy or who have POAG. The results of this study could lead to the design of a drug to prevent the hyaluronic acid from becoming cut into small pieces. This could be the first treatment that targets the underlying cause of POAG, rather than just managing the symptoms of the disease.
Dr. Knepper’s team has demonstrated that a chemical called low molecular weight (i.e. small size) hyaluronic acid activates the innate immune system in cell culture. The team now can block this response through a drug known as naloxone, which prevents an immune response to small hyaluronic acid fragments and the resulting cell death in culture. They are also setting the stage for testing another drug to prevent the breakdown of hyaluronic acid into toxic lower molecular weight fragments. They anticipate that the combination of these two prototype drugs will act in concert and thereby achieve the goal of saving the eye from the damage caused by POAG. This could be the first treatment that targets the underlying cause of POAG, rather than just managing ntraocular pressure.
Dr. Knepper is an ophthalmologist and cell biologist at the University of Illinois at Chicgo and Northwestern University Medical School. Dr. Knepper laboratory has discovered several biomarkers of the glaucoma process which has lead to a possible pathway for understanding the cause and novel treatments of the disease. The BrightFocus grant will enable his research team to test the new unified pathway and explore new treatment modalities based on the innate immune system.