Thursday, November 21, 2024
11/21/2024
Project Summary/Abstract Lyme disease is a tick-borne disease caused by the spirochete Borrelia burgdorferi sensu lato (Bbsl) and is the most prevalent tick-borne disease in the United States. The latest surveillance from the CDC reported that Lyme disease affects more than ~475,000 people in the U.S. every year, a nearly 50% increase from 2015. Furthermore, the disease is expanding from its endemic areas in the Northeast, mid-Atlantic, and Upper Midwest. The rapidly increasing public health risks and rising healthcare costs associated with the disease are exacerbated by controversies surrounding its diagnosis and treatment. While the under-diagnosis of Lyme disease has led to under-treatment, the mis-diagnosis and mis-treatment of the condition have led to serious morbidity as well. Simply put, our current fundamental understanding of the diagnosis, pathophysiology, and treatment of Lyme disease is lacking. Taken together, the data indicate that the development of tools for the non-invasive molecular imaging of Lyme disease is an urgent scientific and clinical need. This R01 proposal is focused on the synthesis, characterization, and in vivo validation of first-in-class radiopharmaceuticals for the PET imaging of Lyme disease. The target for these agents will be VlsE, a protein that is abundantly expressed on the surface of Bbsl throughout its time in its vertebrate host. Specific Aim 1 (SA1) will be focused on the synthesis, chemical characterization, and in vitro biological evaluation of 89Zr- labeled monoclonal antibodies and 68Ga-labeled single domain antibodies capable of binding VlsE with high specificity, selectivity, and affinity. Specific Aim 2 (SA2) will be centered on interrogating the in vivo performance of these VlsE-targeted radiopharmaceuticals in two murine models of Lyme disease. First, we will use mice subcutaneously inoculated with cultured Bbsl to interrogate the sensitivity and specificity of the radioimmunoconjugates and to assess the power of the imaging agents as tools for monitoring response to antibiotic therapy. Subsequently, we will explore the performance of the VlsE-targeted PET probes in a more advanced murine model of Lyme disease: mice infected multiple strains of Bbsl via Ixodes scapularis ticks. In both models, longitudinal PET data will be used alongside a battery of ex vivo analytical techniques to evaluate the ability of the radiotracers to delineate sites of active infection. Ultimately, we contend that a Bbsl-targeting radiotracer could have a paradigm-shifting impact on both the basic science and clinical study of Lyme disease. In the laboratory, a VlsE-targeted radioimmunoconjugate could be a valuable non-invasive tool for studying the dissemination, pathophysiology, and treatment of Bbsl infections in murine models of disease. In the clinic, a Bbsl-targeted radiopharmaceutical could be an indispensable research tool to support the clinical development of novel vaccines, therapeutics, and diagnostics as well as an effective imaging agent to monitor the therapeutic response of patients with particularly persistent or severe Bbsl infections.
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