Engineered cells as agents of arthritis therapy governed by artificial signaling

Project Summary Osteoarthritis (OA), a leading cause of years lost to disability worldwide, is characterized by the breakdown of the collagen II-rich matrix of articular cartilage, infiltration of immune cells, and inflammation of joint tissues such as the synovium. Because no disease-modifying drugs exist to treat arthritis, surgery is the eventual result for patients with progressive OA. Though current biologic therapies for treating OA offer some clinical benefit, outcomes deteriorate over time due to the inability of these approaches to induce robust, sustained regeneration of cartilage and stabilization of joint tissues. Investigational cell engineering strategies have been developed to overcome the limitations of current regenerative medicine approaches, but these strategies fail to regulate cell functions based on reliable signatures of disease. Lack of such disease-dependent regulation of cell behaviors can lead to aberrant cell activities that negatively impact health or fail to mitigate disease. Here, we propose to leverage advanced cell design platforms to confine expression of transgenes to sites characterized by joint degeneration. Our approach builds on our use of a customized cell sense and response system in musculoskeletal bioengineering. This synthetic biology signaling system enables us to enlist cells as programmable agents that implement defined regenerative procedures when they encounter selected features of a microenvironment. Our prior studies have illustrated that exposed collagen II serves as a diagnostic hallmark of OA. This proposal capitalizes on our recent demonstration that an engineered synthetic receptor designed to detect collagen II selectively licenses mesenchymal stem cells to detect damaged cartilage and then upregulate expression transgenes known to promote cartilage synthesis and attenuate inflammatory signaling associated with OA. The overall goal of our work is to establish synthetic receptor-controlled, joint-resident cells as agents to coordinate cartilage repair and antagonize inflammation in the arthritic joint. This project will characterize the ability of our receptors to drive T cells and synoviocytes to mediate cartilage repair in an in vitro model of arthropathy (Aim 1) and will assess the ability of transplanted, synthetically programmed cells to detect and respond to cartilage degeneration in an in vivo model of post-traumatic OA (Aim 2). Finally, Aim 3 will establish feasibility of deploying this technology in the context of an off-the-shelf gene therapy capable of programming cells in situ to respond therapeutically to damaged cartilage.