Activation of Innate Immune Toll-4 Receptor in POAG

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.

Progress Updates

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 intraocular pressure.