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Tracking Down an Aneurysm

A team from the CEA Frédéric-Joliot Institute has developed new optical probes for non-invasive imaging. These chemical tools could lead to the development of diagnostic agents to better characterize the risk of aortic aneurysm.
Published on 5 May 2017

In the case of processes that require tissue remodeling, such as scarring and embryonic growth, proteins ensure the rearrangement of the joining matrix between cells. These proteins are called metalloproteases of the matrix, or MMP. The first MMP was identified in lizards, whose tails regrow when they are cut off. Today, we know that there are 23 different MMPs in humans. "These MMPs are secreted in an inactive form and activate if necessary," said Laurent Devel, researcher at the Frédéric-Joliot Life Sciences Institute. "Ensuring that MMPs intervene only when needed and do not disintegrate tissues requires subtle control mechanisms." When there is an imbalance between the active and inactive forms, it is completely anarchic.

MMPs were observed to have an anarchic activity in a number of cancers and in pathological processes with inflammatory components. Early clinical trials conducted in the late 1990s and targeting MMPs to prevent the growth of cancer cells yielded counterintuitive results. "Since then, we have witnessed a paradigm shift. We know that in a given pathological context, certain MMPs support the development of the disease, while some others actually do the very opposite," Devel explained. "Before considering any therapeutic intervention, we need to acquire a better understanding of the functional role of each MMP. This requires chemical tools targeting a specific MMP. Such tools could also allow us to perform a more precise diagnosis of the current stage of the pathological process." In collaboration with researchers from Yale University, a research team from the Frédéric-Joliot Institute chose one of the MMPs known as "macrophage elastase": MMP12. This enzyme is involved in a number of inflammatory processes such as emphysema, asthma, atherosclerosis and aortic aneurysm (an enlargement of the thoracic aorta that can lead to its rupture). "We identified a ligand that selectively recognizes MMP12," said Devel. "We grafted a fluorescent 'tag' on that ligand to track it by optical imaging." After showing that its recognition properties with respect to MMP12 were unaffected, the scientists tested their probes in a murine aneurysm model in which MMP12 was overexpressed. "Until now, imaging agents tested in preclinical models were meant to follow all MMPs at the same time," Devel said. "The tools we have developed allow us to observe MMP12 more specifically." These results could lead to the development of new tracers for the molecular imaging of MMP12 in humans. Such imaging agents would not only make it possible to diagnose the risks of aneurysm more accurately, it would also allow to better evaluate the effectiveness of treatments.

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