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First genome editing on blood vessel walls

Researchers have developed a unique nanoparticle to deliver genome editing technology to endothelial cells. This is the first time that vascular endothelial cells have been reached for genome editing.

The vascular endothelium

The vascular endothelium is a monolayer of endothelial cells that lines the luminal surface of blood vessels. It plays an important role in vascular homeostasis, helps maintain an anti-thrombotic and anti-inflammatory state and controls the underlying vascular smooth muscle cells. Endothelial cells can also mediate a host of biological functions, including endocytosis and metabolism. They are also involved in organ regeneration and repair as they are activated under adverse conditions. Endothelial dysfunction is involved in many diseases including cardiovascular diseases, sepsis, acute respiratory distress syndrome and COVID-19 respiratory distress.

CRISPR-Cas9 technology holds great promise for treating human disease. The recombinant adeno-associated virus (AAV) is typically used as a delivery system for such technology with good in vivo genome editing efficacy. However, this vector is capable of triggering high immune response and has a low packaging size. As a result, attention has turned to the use of nonviral vectors. Lipid nanoparticles in particular have garnered attention having previously obtained efficient genome editing in the liver. Nonetheless, this delivery system remains a challenge for other organs, and the ability to induce robust genome editing of the vascular endothelium has been difficult.

A vascular delivery system

In a recent study, published in Cell Reports, researchers reported the development of a powerful new delivery system for genome editing in vascular endothelial cells. More specifically, they developed poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG-b-PLGA) copolymer-based nanoparticles formulated with polyethyleneimine.

The team found that a single administration of the nanoparticle carrying CRISPR/Cas9 plasmid DNA resulted in highly efficient genome editing in vascular endothelial cells. This included in the lung, heart, aorta and peripheral vessels of adult mice.

To investigate this further, they performed western blotting and immunofluorescent staining where they demonstrated an ~80% decrease of protein expression selectively in endothelial cells. This resulted in a phenotype mimicking that of genetic knockout mice.

In addition, the researchers also observed that nanoparticle delivery of plasmid DNA could induce genome editing of at least two genes or introduce genome editing and transgene expression in endothelial cells simultaneously.

Altogether, this study demonstrates that nanoparticle delivery of CRISPR/Cas9 is a powerful tool to rapidly and efficiently alter expression of genes in vascular endothelium. This holds promise for cardiovascular research by not only facilitating investigations into molecular mechanisms underpinning the disease but by also advancing treatment.   

Senior author, Youyang Zhao, expressed:

“With this nanoparticle we can introduce genes to inhibit vascular injury and/or promote vascular repair, correct gene mutations and turn genes on or off to restore normal function. It also allows us to edit multiple genes at the same time. This is an important advance for treating any disease caused by endothelial dysfunction.”

Image credit: canva

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Blood / CRISPR / Genome Editing