Biosensor-based cell therapies for the treatment of experimental liver injury, muscle atrophy and diabetes

Abstract

Mammalian synthetic biology aims to program and probe mammalian cell behavior in order to achieve novel or desirable functionalities. Advances in this field have led to a variety of sophisticated synthetic biological components and systems that opened up many new doors for the development of novel gene- and cell-based therapeutic and diagnostic products as alternative strategies to conventional medicine. However, when translating these gene- and cell-based products into humans, one significant issue to be considered is the potential immunogenicity, even with encapsulated cellular implants. For example, the xeno-antigens may trigger host immune response and affect the products’ safety and efficacy after transplantation. Since the human body itself owns a library of receptors for detecting changes in its physiological state or for detecting external stimuli, we can take advantage of our own sensing molecules as a rich resource for the design of synthetic gene networks and therapeutic products that are immune-compatible. To fulfill this aim, this thesis is dedicated to exploring the potential of using human receptors as core-building blocks for cell- and gene- based therapy to solve real-world medical problems. In this work, the individual chapters will illustrate two detailed examples on how to rewire human receptor-based signaling pathways for engineering cell therapeutics: (1) A closed-loop synthetic gene circuit using human bile acid receptor TGR5 as a sensor for liver injury, providing early detection of liver injury and performing automatic treatment; (2) An open-loop synthetic gene circuit using human menthol and cold receptor TRPM8 for the construction of a fully human transgene switch to regulate therapeutic release via cooling sensation. Finally, a conclusion is drawn to discuss the advantages and disadvantages of the current work as well as its potential in future development and for the translation from bench to bedside.