Thursday, November 21, 2024
11/21/2024
Project Summary The long-term goal of my lab is to develop durable cell-based therapies for treating various chronic diseases. Engineered cells secreting therapeutic proteins are grafted into the body to act as biological drug-factories and provide an attractive strategy for long-term cure of diseases such as hemophilia, diabetes, and liver disorders. ‘Off-the-shelf’ therapeutic cells are immunogenic to the host and must be protected from the host immune system. Cell-encapsulation systems physically isolates the graft from components of the host immune system and provide a safe and effective way to transplant allogenic cells without systemic immunosuppression. Unfortunately, despite decades of intense research, the goal of developing an encapsulated cell-based therapy that remains functional in humans long-term has yet to be realized. Two core challenges to the proper function of encapsulated cells in vivo are 1) Activation of the host immune system (innate and adaptive) resulting in foreign-body reactions (FBR) to the implant leading to fibrosis and cell death, and 2) cellular dysfunction and death due to hypoxic and pro-inflammatory environments. Research efforts to combat these challenges have primarily focused on material innovation, while very little attention has been given to engineering cells and system that function synchronously. The changes in cellular processes within the graft in vivo and how the graft interacts with the host immune system remain a black box. Over the next five years, my lab’s research will aim to fill this knowledge gap in our understanding of cellular behavior in vivo and engineer cells and systems that are designed to survive and function within the body for long periods. We hypothesize that by systematically engineering the cellular hosts and the encapsulation system, we will be able to improve efficacy, extend the lifetime, and expand the range of applications of cell-based therapies. To do this, we will pursue three independent research directions, which can be synergistically combined to derive superior cell therapy products. First, we will uncover pathways responsible for the death and dysfunction of transplanted cells allowing us to engineer resilient cells suitable for long-term survival in vivo. Next, we will engineer stealth by reducing the immunogenicity of the implant and presenting tolerogenic cues to the host immune system. Finally, we aim to build function into these implants by incorporating advanced features to allow the retention of these devices on soft organs such as the liver and heart. Given the broad challenges presented by encapsulated cell systems in vivo, these future efforts are well-suited to the research program, as they utilize a widely applicable multiscale and multi-disciplinary experimental framework.
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