MARCKS: A novel therapeutic target in uveitis

Biomarck Pharmaceuticals, Ltd, Durham NC

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT 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-?B. 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-?B 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 ? 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.