Uveitis, the most common form of intraocular inflammation, accounts for 10-15% of preventable blindness in the US. Treatment options are limited to cortiscosteroids and/or immunosuppressants, but both of these therapies show limited efficacy and are associated with numerous adverse and potentially serious side effects. New therapeutic targets leading to effective and safe treatments are urgently required. A novel potential therapeutic target to treat uveitis is Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS). Uveitis, both acute and chronic, is characterized by an inflammatory response involving an influx of leukocytes, production of pro-inflammatory cytokines, and activation of NF-κB. Interestingly, these same responses in another organ, the lung, characterize pulmonary inflammation and development of acute respiratory distress syndrome (ARDS). We have found that inhibiting MARCKS in the lung via administration of a MARCKS-inhibitory peptide, named BIO-11006, ameliorates inflammation and reverses development of ARDS in mouse models of the disease, and does so by inhibiting leukocyte influx, pro-inflammatory cytokine production, and NF-κB activation. Given similarities in the inflammatory processes in the eye in uveitis and the lung in ARDS, we looked in a pilot study at the effects of treating uveitis in the lipopolysaccharide (LPS) rabbit model of the disease with intravitreally-injected BIO-11006. This treatment dramatically blocked leukocyte influx and attenuated inflammation in the LPS rabbit model. In this application, we wish to expand on these preliminary findings and provide proof-of-concept that inhibition of MARCKS function by intravitreally â injected BIO-11006 can ameliorate inflammation in the eye. The hypothesis is that treatment of either LPS-inflamed rabbit eyes (a model of acute uveitis) or experimental autoimmune uveitis (EAU) rat eyes (a model of chronic uveitis) with BIO-11006 will inhibit or reverse, in a concentration- and time-dependent manner, the inflammatory response. The aims are: 1) To determine whether treatment of rabbits with intravitreal injection of BIO-11006 at selected time points after development of acute uveitis via LPS administration will attenuate, in a time- and concentration-dependent manner, the acute inflammatory response; and, 2) To determine whether treatment of rats with intravitreal injection of BIO-11006 at selected time points after development of chronic uveitis via sensitization with Interphotoreceptor Retinoid Binding Protein (IRBP) will attenuate, in a time- and concentration-dependent manner, the chronic inflammatory response. Successful proof-of-concept in these studies can set the stage for further development of a new treatment for uveitis in either injectable or topical application (e.g. eye drop) form.
Public Health Relevance Statement: Narrative: Uveitis or eye inflammation can lead to ocular problems and even blindness, but currently the treatments for this disease are not that effective and have serious side effects, so new therapies are needed. We have found that drugs that target a protein called MARCKS (myristoylated alanine-rich C-kinase substrate) have strong anti-inflammatory effects in other organs, such as the lung, and here we wish to determine if a drug that is an effective anti-inflammatory treatment in the lung, and in fact is currently in clinical trials in human patients with a type of lung inflammatory disease, can also be effective in uveitis. The drug will be tested for anti- inflammatory properties in two animal models of uveitis, one for the acute and the other for the chronic form of the disease.
Project Terms: Acute; Address; Adult Respiratory Distress Syndrome; Affect; Animal Model; Anterior; Anterior uveitis; Anti-inflammatory; Antiinflammatory Effect; Attenuated; Autoimmune Process; autoimmune uveitis; Blindness; Cataract Extraction; cell motility; Cells; Chronic; Clinical Trials; cytokine; Cytokine Activation; Development; Disease; Disease model; Drug Targeting; Eye; Eyedrops; Future; Human; IL8 gene; Immune; Immunological Models; Immunosuppressive Agents; Inflammation; Inflammatory; inflammatory lung disease; Inflammatory Response; Inhalation; Injectable; Injury; interstitial retinol-binding protein; intravitreal injection; Laboratories; Lead; Leukocytes; Lipopolysaccharides; Lung; MARCKS gene; Mediating; Modeling; mouse model; Names; new therapeutic target; novel; novel therapeutics; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Patients; Peptides; Pharmaceutical Preparations; Phase; phase 2 study; Pilot Projects; Posterior eyeball segment structure; Prevalence; Process; Production; Property; Proteins; Pulmonary Inflammation; Rattus; Recurrence; Research; response; Route; Secondary to; side effect; Small Business Technology Transfer Research; Steroids; Syndrome; Systemic disease; Testing; Therapeutic; therapeutic target; Therapeutic Uses; Time; TNF gene; Topical application; Uncertainty; Uvei
