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CRISPR genome editing in adult vascular endothelium

Commented by the ESC WG on Development, Anatomy & Pathology

Basic Science - Cardiac Diseases - Gene Therapy, Cell Therapy
ESC Working Groups

Every year. the advances of single cell genomics generate vast amounts of data and myriads of targets to be further studied, but the generation of strong and reliable mouse transgenic mice to do so, even in the times of CRISPR, is long and time consuming. In a recent paper published in Cell Reports1, Zhang and colleagues report a method to target specifically the endothelium for robust genome editing. The specific targeting of endothelial cells is of importance because the vasculature plays a crucial role maintaining homeostasis in the body in general, and in the heart in particular. Moreover, heart failure is well known to be associated with vascular dysfunction and the restoration of a healthy endothelium and microcirculation represents a valuable therapeutic strategy to treat cardiac disease 2. Furthermore, the endocardium and the coronary endothelium are crucial for during heart regeneration 3–5.

For these reasons, the authors of this report have developed a poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG-b-PLGA) copolymer-based nanoparticle formulated with polyethyleneimine that distributes throughout the body and does not accumulate in the liver. These nanoparticles are injected retro-orbitally into the mouse and, interestingly for our working group, they can be detected in the aorta and in the heart. This novel development might prove to be of great interest for the study of cardiovascular biology as current methods, like adeno-associated virus (AVV) or lipid-modified nanoparticles, could either trigger an immune response 6 or yield low efficient genome editing rate 7.

The nanoparticles employed by Zhang and colleagues have high packaging capacity and in order to target the endothelial cells they are loaded with a CRISPRCDH5 plasmid that expresses Cas9 under the control of the endothelial specific Cdh5 promoter. In this report, the authors targeted the expression of Pik3cd gene, that encodes the p110γ isoform of PI3K. After performing a dose analysis and qPCR validation in isolated ECs, the authors report that injecting 40 µg of plasmid per adult animal induces a reduction of around 50% of Pik3cd gene expression and around 80% of p110γ protein expression in endothelial cells isolated from the lung. The authors compared then the phenotype induced by Pik3cd-nanoparticles treatment in mice with the phenotype previously observed in Pik3cd knockout mice. They report that after LPS treatment, both conditions show similar vascular response. Interestingly the authors have also shown that two genes can be modified at the same time using the system reported in their article.

The method presented by Zhang and colleagues opens a door for different applications that range from the study of heart regeneration to the generation of therapeutical tools for vascular diseases by genome editing and gene transfer. In addition, given the presence of endothelial cells in all organs and its intimate relationship with the other parenchymal cells, these nanoparticles could be used beyond the vasculature by making endothelial cells express secreted molecules that could act beneficially on the other cells of the target organ.


  1. Zhang, X. et al. Robust genome editing in adult vascular endothelium by nanoparticle delivery of CRISPR-Cas9 plasmid DNA. Cell Reports 38, 110196 (2022).
  2. Luxán, G. & Dimmeler, S. The vasculature: a therapeutic target in heart failure? Cardiovascular Research (2021).
  3. D’Amato, G. et al. Endocardium-to-coronary artery differentiation during heart development and regeneration involves sequential roles of Bmp2 and Cxcl12/Cxcr4. 2021.10.25.465773 (2021) doi:10.1101/2021.10.25.465773.
  4. Münch, J., Grivas, D., González-Rajal, Á., Torregrosa-Carrión, R. & de la Pompa, J. L. Notch signalling restricts inflammation and serpine1 expression in the dynamic endocardium of the regenerating zebrafish heart. Development 144, 1425–1440 (2017).
  5. Marín-Juez, R. et al. Coronary Revascularization During Heart Regeneration Is Regulated by Epicardial and Endocardial Cues and Forms a Scaffold for Cardiomyocyte Repopulation. Dev Cell 51, 503-515.e4 (2019).
  6. Mingozzi, F. & High, K. A. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 122, 23–36 (2013).
  7. Luo, Y.-L. et al. Macrophage-Specific in Vivo Gene Editing Using Cationic Lipid-Assisted Polymeric Nanoparticles. ACS Nano 12, 994–1005 (2018).
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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