Adiponectin Biology and Dry Eye Disease
Adipose tissue is not simply an inert storage depot for lipids but is also an important endocrine organ producing hormones that plays a key role in the integration of endocrine, metabolic, and inflammatory signals for the control of energy homeostasis and the overall inflammatory state. These bioactive proteins have been collectively named adipocytokines. Over the past 20 years, adiponectin has gained considerable attention as an important protective adipocytokine that counterbalances the negative effects of obesity induced by other cytokines that amplify inflammatory responses, such as leptin, IL-6, and TNF-a. In contrast, adiponectin is unique in its anti-inflammatory actions, and adiponectin levels are inversely correlated with obesity and diabetes. Animals lacking adiponectin show increased susceptibility to metabolic, inflammatory, and fibrotic diseases, which can be reversed upon replacement. This includes fatty liver disease, atherosclerosis and insulin resistance
Based upon the well-characterized and broad anti-inflammatory effects of adiponectin on multiple organs, investigators tested the hypothesis that adiponectin could be beneficial in dry eye disease, a condition in which alteration in tear production and composition leads to an inflammatory response that further damages the ocular surface via production of pro-inflammatory cytokines and activation of pro-inflammatory white cells. In a mouse model of dry eye disease that mimics human disease, they found that adiponectin protein effectively and significantly reduced the signs of dry eye (demonstrating increased tear production and reduced corneal damage) and decreased pro-inflammatory cytokines and activated white cells.
However, the development of adiponectin protein as a drug complicated by the presence of multiple adiponectin oligomeric isoforms, by its relative insolubility, and by cell-type-specific effects in different tissues.
Allysta is developing a peptide called ALY688 derived from the sequence of the human adiponectin that potently binds to and activates the same receptors as the full length protein. It has been further optimized for stability and suitability for topical administration. In the mouse model of dry eye disease, ALY688 was as effective as the adiponectin protein in improving measures of dry eye disease (including corneal damage and tear film stability) and reduced the inflammatory response.
In addition, ALY688 is also being developed as a sustained release depot formulation suitable for subcutaneous administration and treatment of non-alcoholic steatohepatitis (NASH) and other diseases in which metabolic dysfunction resulting from obesity and diabetes result in serious complications.