MARCKS: A novel therapeutic target in uveitis

ABSTRACT Uveitisthe most common form of intraocular inflammationaccounts forof preventable blindness in the USTreatment options are limited to cortiscosteroids and or immunosuppressantsbut both of these therapies show limited efficacy and are associated with numerous adverse and potentially serious side effectsNew therapeutic targets leading to effective and safe treatments are urgently requiredA novel potential therapeutic target to treat uveitis is Myristoylated Alanine Rich C Kinase SubstrateMARCKSUveitisboth acute and chronicis characterized by an inflammatory response involving an influx of leukocytesproduction of pro inflammatory cytokinesand activation of NFBInterestinglythese same responses in another organthe lungcharacterize pulmonary inflammation and development of acute respiratory distress syndromeARDSWe have found that inhibiting MARCKS in the lung via administration of a MARCKS inhibitory peptidenamed BIOameliorates inflammation and reverses development of ARDS in mouse models of the diseaseand does so by inhibiting leukocyte influxpro inflammatory cytokine productionand NFB activationGiven similarities in the inflammatory processes in the eye in uveitis and the lung in ARDSwe looked in a pilot study at the effects of treating uveitis in the lipopolysaccharideLPSrabbit model of the disease with intravitreally injected BIOThis treatment dramatically blocked leukocyte influx and attenuated inflammation in the LPS rabbit modelIn this applicationwe wish to expand on these preliminary findings and provide proof of concept that inhibition of MARCKS function by intravitreallyinjected BIOcan ameliorate inflammation in the eyeThe hypothesis is that treatment of either LPS inflamed rabbit eyesa model of acute uveitisor experimental autoimmune uveitisEAUrat eyesa model of chronic uveitiswith BIOwill inhibit or reversein a concentrationand time dependent mannerthe inflammatory responseThe aims areTo determine whether treatment of rabbits with intravitreal injection of BIOat selected time points after development of acute uveitis via LPS administration will attenuatein a timeand concentration dependent mannerthe acute inflammatory responseandTo determine whether treatment of rats with intravitreal injection of BIOat selected time points after development of chronic uveitis via sensitization with Interphotoreceptor Retinoid Binding ProteinIRBPwill attenuatein a timeand concentration dependent mannerthe chronic inflammatory responseSuccessful proof of concept in these studies can set the stage for further development of a new treatment for uveitis in either injectable or topical applicatione geye dropform NarrativeUveitis or eye inflammation can lead to ocular problems and even blindnessbut currently the treatments for this disease are not that effective and have serious side effectsso new therapies are neededWe have found that drugs that target a protein called MARCKSmyristoylated alanine rich C kinase substratehave strong anti inflammatory effects in other organssuch as the lungand here we wish to determine if a drug that is an effective anti inflammatory treatment in the lungand in fact is currently in clinical trials in human patients with a type of lung inflammatory diseasecan also be effective in uveitisThe drug will be tested for antiinflammatory properties in two animal models of uveitisone for the acute and the other for the chronic form of the disease