Cell heavyweight: Liu Ruqian develops a new virus-like vector for safe and efficient in vivo gene editing

When it comes to Liu Ruqian, the first thing that comes to our mind are new gene editing tools such as Base Editor and Prime Editor
.

Different from CRISPR-Cas9 gene editing, a series of precise gene editing tools developed by Ruqian Liu's team do not cause DNA double-strand breaks (DSBs) , so they are considered safer and more valuable for clinical applications

Different from CRISPR-Cas9 gene editing, a series of precise gene editing tools developed by Liu Ruqian's team will not cause DNA double-strand breaks (DSBs) .

For gene therapy, in addition to the gene editing tool itself, the delivery vehicle is equally important
.

At present, the delivery vectors in clinical application can be mainly divided into viral vectors (lentivirus, AAV, etc.

On January 11, 2022, David Liu's team published a research paper entitled: Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins in the top international academic journal Cell
.

Liu Ruqian's team developed an engineered virus-like particle (eVLP) that can overcome multiple bottlenecks in protein complex delivery :

Engineered Viroid Particles Engineered Viroid Particles Overcome Multiple Bottlenecks in Protein Complex Delivery Overcoming Multiple Bottlenecks in Protein Complex Delivery

1) eVLPs are DNA-free and directly deliver the ribonucleoprotein (RNP) of the gene editor with minimal off-target;

2) Base editing delivered by eVLP effectively edited 63% of cells in mouse liver and reduced PCSK9 levels in serum by 78%;

3) Base editing delivered by eVLP improves vision in a mouse model of genetic blindness
.

The in vivo delivery of gene editing components in the form of ribonucleoprotein (RNP) has more safety advantages than direct delivery of nucleic acids
.

Gene editing components are delivered in vivo in the form of ribonucleoprotein (RNP), which has more safety advantages than direct delivery of nucleic acids.
Gene editing components are delivered in the form of ribonucleoprotein (RNP) in vivo, compared to direct delivery of nucleic acid.
Delivering nucleic acids with more safety advantages

In this study, Liu Ruqian's team developed engineered DNA-free virus-like particles (eVLPs), which are based on retroviruses with numerous modifications and optimizations to overcome the challenges of packaging, delivery, and release.
The bottleneck, in this paper, is the fourth-generation eVLP, which can efficiently package and deliver base editors and the ribonucleoprotein (RNP) form of CRISPR-Cas9
.

Enables efficient gene editing in human cells, mouse primary cells, and a variety of mouse organs and tissues (liver, brain, eye)

In eVLPs, their cellular and organ targeting can be altered by using different glycoproteins
.

A single injection of eVLPs into mice enables efficient gene editing in different organs

Liu Ruqian's team used eVLP to deliver the base editor's ribonucleoprotein (RNP), which was able to successfully edit 63% of mouse liver cells and reduce the level of PCSK9 protein in serum by 78%
.

The PCSK9 protein expressed by the PCSK9 gene can bind to the LDL receptor (LDL-R) on the surface of hepatocytes to degrade LDL-R, thereby increasing the level of low-density lipoprotein cholesterol in plasma

Cholesterol prevents blood vessels

Liu Ruqian's team also verified the human congenital amaurosis mouse model.

In addition, Liu Ruqian's team also tested the off-target situation of DNA level and RNA level of gene editing delivered by eVLP in vitro and in vivo.

Collectively, these findings demonstrate that engineered virus-like particles (eVLPs) serve as potential therapeutic macromolecule delivery vehicles that combine key advantages of viral and non-viral delivery to deliver gene editing tools To cells and organs, high-efficiency gene editing can be achieved with minimal off-target effects and high safety

Engineered virus-like particles (eVLPs) can be used as a potential therapeutic macromolecule delivery vehicle, which combines the key advantages of viral and non-viral delivery, enabling gene editing tools to be delivered to cells and organs for efficient gene editing, Engineered virus-like particles (eVLPs) can be used as a potential therapeutic macromolecule delivery vehicle, which combines the key advantages of viral and non-viral delivery, and can integrate gene editing tools with minimal off-target effects.

Original source:

Samagya Banskota, et al.

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