Writing 丨 Wang Cong
Edit 丨 Wang Duoyu
WaterwritingCar-T cell therapy has completely changed treatment pattern, especially bloodcancer.However, despite these success, the therapy is still facing some major obstacles, which is still not good for the vast majority of cancer.Recent research shows that this involves the internal dysfunction mechanism of T cells, such as T cell exhaustion and metabolic disorders.
Based on the development of CRISPR-CAS9 gene editing technology, it provides new solutions for the next generation of gene engineering T cell therapy.For example, the specific gene of CRISPR-Cas9 knocks on T cells to enhance anti-tumor activity or generate spot CAR-T cells.At present, a number of new-generation CAR-T cell therapy based on CRISPR-Cas9 has entered clinical trials and showed potential cancer treatment effects.
However, the gene editing system based on CRISPR-Cas9 is still limited in terms of safety, effectiveness and more extensive application potential.CAS9 nucleic acid enzymes and base editors will permanently change the T cell genome. In addition, CAS9 nucleic acid enzymes can also cause a variety of potential gene toxic side effects.
On February 21, 2024, the team of 亓 Lei at Stanford University published a entitled on the top international academic journal Cell ::A Versatile Crispr-Cas13d Platform for Multiplexed Transcriptomic Regulation and Metabolic Engineering in Primary Human T Cells.
该研究开发了一种基于CRISPR-Cas13d的多重RNA 编辑平台——MEGA，用于Multi -transcriptional regulation and metabolic engineering of primitive T cells.
This research has developed multiple effects orientation array (mega), which is a good one.Programming and scalable platforms use CRISPR-CAS13D RNA guidance and RNA targeted activity to regulate T cells in the transcript level.MEGA can achieve quantitative, reversible, and large -scale gene knocks low in human T cells without a targeted or cut genome DNA.
Apply MEGA to the CAR-T cell exhaustion model, to screen the combination of CRISPR to inhibit the upward increase of inhibitory receptors, and find the pairing regulatory factor of T cell function.In addition, the research also realizes the control of drugs approved by FDA to control CAR activation in a manner of receptor non -dependence.Finally, MEGA realizes multiple blocking of immunomically regulating metabolic pathways to enhance the in vitro and body adaptability and anti-tumor activity of CAR-T cells.
In general, the research and development of a multifunctional Crispr-CAS13D platform- MEGA , multi -transcriptional regulation can be performed in the primary T -cells of the human.The study emphasizes MEGAs various T cell engineering applications and solves the key restrictions of CRISPR-Cas9 gene editing technology in CAR-T cell therapy.As a synthetic immunology toolkit, MEGA provides T cells with the ability to apply various applications from basic biology to enhancing cancer immunotherapy.
亓 Lei
On Lei (Lei S. Qi), an associate professor at Stanford University, was born in Weifang City, Shandong Province in 1983. He graduated from Tsinghua University undergraduate.Professor Zhu Xiwen After graduating from the masters degree, under the suggestion of Professor Zhu Xiwen, Li Lei entered the field of biological engineering across the professional across professionalism and followed the CRISPR gene editing pioneer and the Nobel Prize winner Jennifer Doudna Professor study CRISPR gene editing.
In the field of CRISPR gene editing, Ji Lei can be described as fruitful. As early as February 2013, CAS9 (DCAS9), which was lost for DNA cutting activity for the first time in February 2013, can be used to target DNA sequencesAnd regulating gene expression [2], and on the basis of this, Crispra (gene transcription activation based on CRISPR) and Crispri (gene transcription activation based on CRISPR).These studies of Lai Lei have expanded the CRISPR gene editing to the field of Epico -Epico , which can regulate gene expression without changing the DNA series.In addition, he also developed LiveFish used for real-time imaging for DNA and RNA. It is used to CRISPR-GO in the three-dimensional spatial reorganization genome, miniaturized CRISPR system Casmini system, and new technologies for knocking into and stabilizing large -segments DNA Clip .
In 2022, Ji Lei founded the EPIC BIO of an apparent genetic gene editing company and completed the A round of 55 million US dollars Financing, the company plans to apply the CASMINI system to apparent genetic engineering to develop more secure human genetic diseased therapies.At present, the company treats Facial Habbish Habbing Nutrition (FSHD) Epi-321 is in the IND application. FSHD is caused by lack of methylation in the D4Z4 area, resulting in No. 4The DUX4 genes on the chromosomal are abnormal expression, which targets and restore the methylation of the D4Z4 area through targeted and restored the D4Z4 area, thereby inhibiting the abnormal expression of DUX4, thereby preventing further muscle cell death.
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Thesis link :
1. https://www.cell.com/cell/abstract/s0092-8674 (24)002-8
2. https://www.cell.com/cell/fulltext/s0092-8674 (13) 00211-0