UG3CA268112

Cellular Senescence Network: New Imaging Tools for Arthritis Imaging

Senescent cells play a key role in the pathogenesis of major musculoskeletal diseases, such as chronic inflammatory joint disorders, rheumatoid arthritis (RA), and osteoarthritis (OA). Cellular senescence in articular joints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhanced production of inflammatory cytokines, which in turn perpetuates joint damage and leads to significant morbidities of afflicted patients.

It has been recently discovered that clearance of senescent cells by novel "senolytic" therapies can attenuate the chronic inflammatory microenvironment of RA and OA, and thereby prevent further disease progression and support healing processes. In order to identify patients who might benefit from these new senolytic therapies and to monitor therapy response, there is a significant unmet need in identifying and mapping of senescent cells in articular joints and related musculoskeletal tissues.

To fill this gap, we propose to develop a new imaging biomarker that will significantly improve our capabilities to identify and characterize senescent cells in human musculoskeletal tissues. We have generated exciting preliminary data that show that 3-D-galacto-2-nitropyridine (PYGAL), a known hydrophilic B-gal substrate, can be labeled with 18F-fluorine. Upon intravenous injection, 18F-PYGAL enters senescent cells and is selectively cleaved by B-galactosidase, a senescence-specific enzyme in these cells. The trapped radiotracer can be detected with positron emission tomography (PET) and autoradiography, thereby serving as an imaging biomarker for senescent cells.

We propose to introduce 18F-PYGAL as the first clinically translatable radiotracer which can detect senescent cells in vivo, in bones and joints of animal models and human volunteers. In the initial UG3 phase of our project, we will demonstrate proof-of-principle of this new imaging technology in a mouse model of RA and a large animal model of OA. In the subsequent UH3 phase, we will scale, optimize, and validate 18F-PYGAL PET for mapping human tissues, first in human joint specimens and second in a first-in-human Phase I clinical trial.

At the end of the UH3 phase, we will have delivered a novel imaging tool that can visualize and quantify the presence and distribution of senescent cells in multiple musculoskeletal tissues directly, non-invasively, and longitudinally in vivo. Results will be catalogized in a planned senescence cell atlas and shared with the Cellular Senescence Network.

Our 18F-PYGAL-PET imaging tool will significantly improve upon state-of-the-art imaging technologies for the diagnosis of musculoskeletal disorders, can be integrated with other imaging technologies, such as MRI, and is ultimately capable of being scaled to map senescent cells in multiple human tissues in a high-throughput fashion. Since 18F-PYGAL targets senescent cells in multiple different tissues and can be easily imaged with widely available medical imaging technologies, our proposed new senescence imaging biomarker can be expected to be used widely by tissue mapping centers and relevant research communities.

The Leland Stanford Junior University

NOT APPLICABLE

93.310 - Trans-NIH Research Support

National Cancer Institute (NCI) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

Cellular Senescence Network: Technology Development and Application (UG3/UH3 Clinical Trial Not Allowed) (RFA-RM-21-009)

Amendment Since initial award the total obligations have increased 93% from $549,500 to $1,059,696.