Aptamers targeting fibroblasts in inflammatory arthritis

Inflammatory arthritides are a group of chronic diseases characterized by the inflammation and consequent destruction of the inner lining of joints, in which connective tissue cells known as fibroblasts play a key role. Under certain conditions these cells can become activated causing them to produce proteins that lead to inflammation. Increased production of certain marker proteins has been proposed as indicators for the activation of these cells as shown also by previous studies in our department. Efficient, timely treatment of inflammatory arthritis is severely hampered by the limited efficacy of current medications as well as by the lack of definitive markers of disease activity. Aptamers are single-stranded RNA segments that can be selected to bind various target molecules, including proteins and are advantageous over classical antibodies in many aspects. In this project our aim is to generate highly selective aptamers targeting proteins that are considered to be markers of activated fibroblasts and study their potential as a diagnostic tool and/or therapeutic agent. As our second objective, we aim to identify as of yet unknown surface proteins of activated fibroblasts. To achieve this, we will design aptamers selective for such proteins using purified proteins, mammalian cells which produce these as well as fibroblasts harvested from human tissue removed during joint replacement surgery. To assess the capacity of the developed aptamers as diagnostic tools, we will assess their binding to the target proteins. To evaluate their potential utility as a therapeutic agent we will measure their effect on fibroblast activity and function. The most promising aptamers will be also studied in mouse models of arthritis. Development of aptamers which can neutralize proteins that are known to play a role in the activation of fibroblasts may yield agents with therapeutic implications, while those developed against as of yet unknown markers of fibroblast activation may aid in characterizing the localization of such cells in joints.