Editors' ChoiceMolecular Imaging

Genetic ultrasonic biosensor for picturing proteases

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Science Translational Medicine  12 Aug 2020:
Vol. 12, Issue 556, eabd4775
DOI: 10.1126/scitranslmed.abd4775

Abstract

A genetically encoded biosensor allows noninvasive imaging of protease activity using ultrasound.

Noninvasive assessment of enzymatic activity in vivo could allow routine assay of the health of transplanted tissues and stem cells. Most current molecular imaging strategies for such noninvasive applications are optical, limiting use in deep tissues, or nuclear, generally limiting spatial resolution. To bridge these extremes, researchers have looked to ultrasound, which can image deep tissue processes noninvasively with high spatial and temporal resolution.

In a recent study, Lakshmanan and colleagues used a genetically encoded gas vesicle system with ultrasound to image the activity of specific proteases deep in the gastrointestinal system of mice. In this system, they utilized gas vesicles that they previously engineered to be a genetically encoded ultrasound contrast agent. In prior work, they showed that by changing the protein coat of the gas vesicle they could tune the ultrasound responsiveness of the system, among other features of interest. In this current work, they further engineered this system to contain recognition sequences for target proteases so that, in the presence of a medium containing the protease of interest, the protease degrades the vesicle protein coat, yielding a change in vesicle wall stiffness that can be detected with a specific ultrasound sequence. By looking for this differential ultrasound responsiveness, a user could then effectively visualize the localization of active protease. They validated this approach with three different protease targets and in bacterial systems in vitro, as well as in a microbial transplant in the mouse gastrointestinal lumen. In their in vivo gastrointestinal model, they could differentiate between different cellular populations based on their protease expression activity and identify in which portion of the intestinal lumen the cells resided.

Going forward, it would be of interest to see whether signal fidelity is retained in larger animal systems, given the relatively high ultrasound frequency used in these experiments. An explicit end-use application of this technology in a clinically important scenario, such as tracking the vitality of a solid organ or stem cell transplant, should also be tested. The future of noninvasive high-resolution molecular imaging certainly sounds promising.

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