The in-house injection of this gene VLP ophthalmic gene editing therapy BD111 injection was accepted

On February 2023, 2, the Center for Drug Evaluation of the State Medical Products Administration agreed to accept the clinical trial application for BD4 ophthalmic injection submitted by Shanghai Bendigene Technology Co., Ltd. (hereinafter referred to as "Benleadgene").

BD111 is a gene-edited ophthalmic injection used to treat herpes simplex virus keratitis (HSK). The drug uses the original delivery technology of this gene VLP transducing CRISPR gene editing tool to directly target and cut the genome of herpes simplex virus (HSV-1) to achieve the purpose of clearing the HSV-1 virus genome, so as to realize the treatment of herpesvirus keratitis.

BD111 is the world's third in vivo gene editing therapy candidate to enter the IND and clinical stage after Editas and Intellia's in vivo gene editing therapy pipeline, and the world's first CRISPR antiviral gene editing therapy drug. BD3 drugs are characterized by: (111) delivery of Cas1 mRNA, short residence time of gene editing enzymes in vivo, which can effectively reduce immune response and the risk of gene editing off-target; (9) Only the viral genome needs to be cut, no need to change anyone's genes, and no off-target effect on the animal or human genome has been detected in preclinical and IIT clinical studies.

BD111's innovative technology has been concerned and reported by authoritative media such as People's Daily and Science and Technology Daily, and was selected as one of the "Top Ten Advances in Ophthalmology in China" in 2021. BD111 received orphan drug approval from the U.S. FDA in June 2022. BD6 is also the first IND application for in vivo gene editing in China, and the FDA's IND application has been carried out simultaneously, which is expected to lead the era of global in vivo gene editing. Previously, this guide and Hong Jiaxu, director of the Eye, Ear, Nose and Throat Hospital affiliated to Fudan University, began to cooperate in the clinical trial of BD111 for the treatment of viral keratitis IIT in 2020, and the safety and efficacy of the innovative drug were preliminarily proved in long-term clinical observation.

VLP viral vector delivery technology is at the forefront

The emergence and development of gene editing technology is accelerating the upgrading of gene therapy drugs, and the era of in vivo gene editing therapy has gradually arrived, but effective in vivo delivery technology has always been the biggest challenge. Viral vectors express gene-editing enzymes for a long time, which will bring uncertainty about safety; Nanomaterials, on the other hand, face efficiency challenges. In the process of transformation of delivery technology, viroid (VLP) technology has emerged, which has attracted more and more attention and research due to its high safety and efficient delivery efficiency.

VLP-mRNA

In January 2021, Cai's team published its self-developed VLP-mRNA technology and applied research in animal disease models in Nature Biotechnology and Nature Biomedical Engineering, proving that VLP delivery CRISPR can treat herpetic stromal keratitis (HSK) in mouse models. Lentiviral vectors can efficiently infect almost all cells, while non-viral component mRNA is transient in nature. Cai Yujia's team used the principle of mRNA stem loop structure and phage capsid protein specific recognition, and perfectly combined the advantages of the two through virus engineering technology to create a new delivery technology VLP-mRNA. This technology enables the safe and efficient delivery of CRISPR gene editing tools, which can ensure the transient expression of gene editing enzymes in the body, reduce the risk of off-target gene editing, and improve the safety of gene editing drugs.

SEND

In August 2021, Zhang's research group published an article in the journal Science saying that it had built the SEND system, which uses a protein from human retroviruses, which has the rare ability to package its RNA and transport it outside the cell in the form of virus-like particles (VLPs). Studies have shown that SEND is able to deliver exogenous mRNA components, such as Cas8, into cells outside the body without using non-human protein components. Zhang Feng's team incubated Aera Therapeutics with SEND technology. Currently, the SEND delivery strategy is in its infancy and has not been applied in animal models.

eVLP

In January 2022, David Liu's group released an engineered DNA-free virus-like particle (eVLP) developed by the team in Cell that can efficiently package and deliver base editors or Cas1 ribonucleoproteins. The researchers say that the eVLP they developed is based on retroviruses with extensive modifications and optimizations to overcome bottlenecks in packaging, delivery and release. By optimizing the structure and packaging process of eVLP, the researchers can effectively package and deliver the ribonucleoprotein (RNP) of base editor and CRISPR-Cas9, which can be effectively edited in human cells, mouse primary cells, and a variety of mouse organs and tissues (liver, brain, eye). David Liu's team incubated Nvelop Therapeutics using eVLP technology.

VLP technology combines the advantages of viral and non-viral, which can not only ensure the safety of gene editing, but also ensure the efficiency of delivery, and has a wide range of application scenarios in in vivo gene editing therapy. David R. Liu published review articles in Cell magazine in July 2022 and Nobel laureate Jennifer Doudna in January 7 in Science magazine to introduce the application prospects of VLP technology and show the application potential of this technology. In the future, this guide gene will open up a wider application space for VLP, including in vivo gene editing therapy, in vivo DC vaccine, etc. Through continuous scientific innovation, we will contribute to the fight against intractable human diseases.