ACE2-targeted PET radiotracers for investigating spatiotemporal distribution of SARS-CoV-2 organ injury and therapy response.

项目总结:

PROJECT SUMMARY: The COVID-19 pandemic, caused by the new coronavirus SARS-CoV-2, has had a remarkable impact on public health worldwide with the largest number of cases and deaths reported in the United States. Improved understanding of COVID-19 will accelerate the development of effective therapeutics, which are necessary to fight SARS-CoV-2 including its new variants. The SARS-CoV-2 human receptor ACE2 is central to disease pathogenesis and potential therapies. This proposal focuses on the imaging and therapy of SARS-CoV-2 using a newly developed, ACE2-targeted PET radiotracer and S-protein neutralizing therapies. These therapies include PLGA nanoparticles bearing recombinant ACE2 (rACE2) and a monoclonal antibody (mAb) 5A6 recently developed at UCSF. Although the techniques and therapies proposed are directly applicable to SARS- CoV-2, they will also potentially apply to future coronavirus infections and other diseases driven by ACE2 suppression especially acute respiratory distress syndrome (ARDS). Therapies derived from ACE2 itself also have high impact in the context of SARS-CoV-2 variants that evade vaccines and mAb-based drugs. We recently identified a cyclic, [68Ga]-NOTA modified ACE2 inhibitory peptide ([68Ga]-NOTA-ACE2pep) as a PET radiotracer to study SARS-CoV-2 infection and its treatment in vivo. This radiotracer was developed with the goal of understanding the timing and location of ACE2 suppression in COVID-19, critical in treating infected patients and identifying disease in the lungs, heart, kidneys, gastrointestinal tract and central nervous system. ACE2-specific PET imaging will also help us understand the effects of rACE2/mAb therapies, whose development has lagged behind vaccine rollout. In this proposal, we will first optimize a radiosynthesis of an analogous 18F-labelled tracer namely [18F]AlF-NOTA-ACE2pep and validate its performance in vitro (Specific Aim 1). In Specific Aim 2, we use [18F]AlF-NOTA-ACE2pep to image ACE2 loss in transgenic mice and a COVID-19 murine model. Finally, in Specific Aim 3 we will develop nanoparticle-derived methods to deliver rACE2/ 5A6 and demonstrate suppression of SARS-CoV-2 infection, when therapy is administered around the time of exposure. This treatment effect will be shown in vivo using [18F]AlF-NOTA-ACE2pep. Our 3-year R01 proposal prioritizes methods and approaches that can be developed very quickly, in an effort to impact the COVID-19 pandemic as soon as possible. The principal investigators of this proposal are Drs. David M. Wilson, Robert Flavell, and Tejal Desai (UCSF) and Sanjay Jain (Johns Hopkins); as leaders in the field of infection imaging Drs. Wilson and Jain have worked extensively together. Key infrastructure is already in place at UCSF and Johns Hopkins for the fight against COVID-19. Specifically, Dr. Jain's BSL3 facility at Johns Hopkins is one of the few places in the world where the proposed PET-CT studies of SARS-CoV-2 infected animals can be performed. We will therefore harness the strengths of multiple productive laboratories at UCSF and Johns Hopkins to accomplish the proposed work.