Vascular endothelial cells serve as a protective barrier in blood-vessel walls and serve as an active source for the synthesis, metabolism, uptake, storage, and degradation of a number of vasoactive substances. Endothelial cell damage can be a factor in diseases. The endothelium is directly involved in peripheral vascular disease, stroke, heart disease, diabetes, insulin resistance, chronic kidney failure, tumor growth, metastasis, venous thrombosis, and severe viral infectious diseases. Now a new mouse study demonstrates how the vascular endothelial cells could be reached for genome editing.

Their findings are published in the journal Cell Reports in a paper titled, “Robust genome editing in adult vascular endothelium by nanoparticle delivery of CRISPR-Cas9 plasmid DNA,” and led by Youyang Zhao, PhD, from Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“Vascular endothelium plays a crucial role in vascular homeostasis and tissue fluid balance,” the researchers wrote. “To target endothelium for robust genome editing, we developed poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG-b-PLGA) copolymer-based nanoparticle formulated with polyethyleneimine.”

Zhao and researchers developed a nanoparticle to deliver genome editing technology, including CRISPR/Cas9, to endothelial cells. This is the first time that vascular endothelial cells could be reached for genome editing, since the usual way to deliver CRISPR/Cas9, does not work for this cell type.

“The nanoparticle we developed is a powerful new delivery system for genome editing in vascular endothelial cells, and could be used to treat many diseases, including acute respiratory distress syndrome from severe COVID-19,” said Zhao. “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.”

Zhao explained that genome editing in endothelial cells may even treat cancers by cutting off the blood supply to the tumor or blocking cancer metastasis. Zhao also noted that their nanoparticle delivery system for genome editing and transgene expression is an advance for cardiovascular research.

“Western blotting and immunofluorescent staining demonstrated an ∼80% decrease of protein expression selectively in ECs [endothelial cells], resulting in a phenotype similar to that of genetic knockout mice,” the researchers wrote.

“Nanoparticle delivery of plasmid DNA could induce genome editing of two genes or genome editing and transgene expression in ECs simultaneously. Thus, nanoparticle delivery of plasmid DNA is a powerful tool to rapidly and efficiently alter expression of gene(s) in ECs for cardiovascular research and potential gene therapy,” concluded the researchers.

Preclinical testing will be needed before clinical trials can begin.

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