Purpose:
This initiative will support the engineering of immune cells to target the human pancreatic compartment to report on previously inaccessible information about diabetes initiation and progression, and/or to deliver environment-specific therapeutic responses to restore islet health and prevent the progression to T1D.
Background:
Type 1 Diabetes (T1D) is a progressive immune-mediated disease that is preceded by an asymptomatic period of highly variable duration in humans. Currently, it is known that 80% of individuals with genetic risk and autoantibodies of two or more different specificities will progress to symptoms within 10 years. Means to detect disease initiation prior to the development of a widespread beta cell-centric autoimmune response could facilitate the use of early therapeutic regimens to prevent the progression to early stage T1D. Critical to the development of these alternative therapeutic strategies is the identification of cellular or molecular biomarkers of early pathogenesis in and around the pancreas, to include alterations in islet health or changes in interactions between the immune and the pancreatic (or peri-pancreatic) compartments. The minuscule amount of pancreatic islet tissue makes it extremely difficult to detect molecular signals specific for beta cell stress or cellular immune responses in peripheral blood. An outstanding challenge for early detection of T1D is to develop non-invasive strategies to report on a disease environment developing in a small tissue compartment nested within the deeper layers of the body.
What triggers the T1D autoimmune response or maintains its progression is still unclear, but beta cell stress is thought to be important. The barriers to the discovery of natural biomarkers of beta cell stress or injury mentioned above lead us to propose the development of synthetic sentinels and early treatment-delivery tools. Such tools could be engineered to home to the pancreatic tissue, detect the appearance of cellular stress, inflammation or damage during the earliest stages of the disease process, report on these events, and ultimately, deliver commensurate therapeutic interventions. Immune cells, with their natural ability to circulate in blood and tissues, to home to specific cellular compartments, and to sense and respond dynamically to their environment, are an ideal candidate for engineering cell-based sentinels that can home to the target tissue to monitor and possibly correct early disease events. Immune cells can be isolated from peripheral blood, genome-edited and amplified in vitro, and re-infused in the donor. Specifically, immune cells could be engineered to home to the pancreatic or islet tissue compartment, to sense and respond quantitatively and proportionally to a dysregulated environment by producing a unique and easily detectable synthetic signal, and to deliver a therapeutic response. Recent years have seen considerable progress in the engineering of synthetic receptors and gene circuits to provide immune cells with sensing and biological response capabilities not found in nature. For example, the expression of synthetic receptors on T cells that recognize specific cancer epitopes are already resulting in spectacular therapeutic breakthroughs and FDA approvals. These synthetic immunology tools can now be applied to the development of cell systems for early monitoring of the T1D disease environment and for the delivery of a therapeutic response that is specific and proportional to the type of tissue damage, inflammation or autoimmune attack characteristic of the early stages of T1D pathogenesis.
Key Dates:
URL for more information:
https://grants.nih.gov/grants/guide/rfa-files/RFA-DK-21-005.html
Filed Under: Funding Opportunities