In recent years, gene editing technology represented by CRISPR-Cas9 has brought revolutionary changes to life medicine. People have high hopes for new technologies such as gene editing and gene therapy, and they look forward to showing success in clinical treatment and conquering chronic diseases.
In January 2018, the United States announced that it would invest US$190 million in the next six years to support somatic gene editing research to develop safe and effective gene editing tools to treat more human diseases. The United States is not hesitating to develop gene-editing technology, which is obviously very optimistic.
In the past two years, China's policy releases in the field of precision medicine have also been very intensive, and a lot of support has been given to technologies such as gene editing. For example, precision medicine will be upgraded to a national strategy, and it is planned to invest 60 billion yuan in 2030. In April 2017, the "Thirteenth Five-Year" Biotechnology Innovation Special Plan was issued, pointing out the development of "a new generation of genetic manipulation technology" .
Specifically, it is necessary to develop precise or quantitative new gene manipulation technology, eukaryotic cell gene (group) editing technology, new microbial gene recombination technology with important application value in industrial production and environmental protection, and promote a variety of genes (group) ) The integration of editing methods, pay attention to the efficiency and throughput of gene manipulation, improve ease of operation, reduce off-target, and expand the scope of application.
According to the latest report of the China Business Industry Research Institute, the global precision medicine market will grow at an annual rate of 15% from 2016 to 2020. The global precision medicine market is expected to exceed 100 billion in 2020 , reaching 105 billion U.S. dollars. "Gene scissors" will be a key to leveraging the 100 billion-level market.
Next-generation CRISPR technology
At present, as a branch of precision medicine, gene editing has an incomplete industry chain, and more of a technological breakthrough and update iteration. The emergence of new genome editing technologies, such as ZFNs (zinc finger nucleases), TALENs (transcription activator effector nucleases) and the CRISPR-Cas9 system have opened up new avenues in the field of gene therapy. Because they can edit targeted sites with simple operation, precise targeting and low cost, they avoid the traditional reliance on homologous recombination, low efficiency, time-consuming and complex disadvantages, and they are becoming the darling of a new generation of gene therapy.
The picture above shows the three modes of CRISPR working
The figure above shows the general flow of gene editing therapy
Research results also continue to confirm the bright prospects of gene editing in clinical treatment. For example, TALEN targeted therapy for Duchenne muscular dystrophy (DMD), ZFN therapy for Parkinson's (PD), TALEN or ZEN are all expected to treat epidermolysis bullosa and α1-Antitrypsin deficiency, TALEN or CRISPR-Cas9 to treat sickle cell anemia, CRISPR-Cas9 to treat genetic tyrosinemia, cataracts, etc.
Compared with the previous two generations of gene editing technologies, ZFN and TALEN, CRISPR technology has more precise positioning of specific DNA and lower cost, which will help gene therapy to reach the general public. It is understood that every time ZFN gene editing is performed. The purchase of zinc fingers only costs US$5,000, while the third-generation CRISPR/Cas9 technology only needs to order a piece of guide RNA, which costs about US$30, which is obviously more cost-effective.
According to a survey conducted by consulting firm BCG, patented technologies developed based on gene editing have experienced a spurt of growth in the past five years, with a growth rate of 41% from 2010 to 2014. Among them, CRISPR technology has developed the fastest, TALEN and ZFN are slightly behind, and the patent subjects include scientific research institutions and enterprises, indicating that the technology has been transformed from pure academic research to commercial application and quickly promoted.
In 2017, in addition to CRISPR-Cas9, the gene editing system was more complete, and some new and improved technologies came into view, which not only improved editing efficiency, reduced off-target effects, but also became safer. The CRISPR-Cpf1 gene editing system is a new generation of gene tools. Cpf1 is also called Cas12a, which is simpler than the Cas9 system, and has a smaller protease, which is easier to deliver into the cell, and the final cutting site is more precise. Based on many advantages, researchers will certainly carry out more research around CRISPR-Cpf1. In addition to editing DNA, a CRISPR-Cas13 tool that can target RNA editing has also been discovered, which can play a role in mammalian cells. There are also many improvements to Cas9, with the goal of making gene editing more accurate and safe.
Global development is in full swing
Shell Club has sorted out foreign gene editing related companies (see the table below). From the table, it can be seen that 6 of the 17 companies have been listed , and most of them are headquartered in the United States. It can be seen that the United States is still at the forefront in the field of gene editing technology. The technologies used by various companies also cover almost three generations of editing technologies, but CRISPR is still the mainstay. In addition, adenovirus or adeno-associated virus technologies are also more common. Secondly, the emergence of CAR-T combined with CRISPR technology indicates that combined therapy will become one. Kind of new trend. Finally, Associate Professor Han Chunyu of Hebei University of Science and Technology claimed to have discovered a new nuclease Argonaute that is different from CRISPR. Although it has attracted global attention and attracted Danish Novozymes to seek cooperation, the discovery has not been recognized so far, and it is even suspected of academic fraud.
China becomes a strong rival of the U.S.
Although the level of gene editing in the United States is among the highest in the world, China's technology in this field is also world-leading. The US media even claimed that "the development of Chinese gene editing technology is beyond the reach of the United States." According to media reports on January 23, 2018, Wu Shixiu, the director and oncologist of Hangzhou Cancer Hospital, has tried to use CRISPR-Cas9 technology to treat patients with esophageal cancer since March last year .
China is the first country in the world to use CRISPR in human trials. So far, at least 86 Chinese patients have received gene editing therapy . The main reason why the United States has lost its leading edge is that the United States has stricter supervision, which requires various risk assessments and safety inspections to ensure patient safety as much as possible before gene editing treatment can be implemented. There is no doubt that China will become a strong opponent of American gene editing technology.
According to incomplete statistics, there are 21 companies involved in gene editing in China, most of which focus on technical support and service outsourcing. Clients come from medical institutions, companies, scientific research institutes and universities, etc. It can be seen that the gene editing technology itself is relatively mature in China. High acceptance.
Analyze the future development trend of gene editing. First, the combination of gene editing technology and CAR-T is expected to become a breakthrough in immunotherapy . In 2015, it was reported that gene editing combined with CAR-T technology successfully saved the life of a child with leukemia. Among them, the TALEN-edited T cells produced by Cellectis are used; and as the earliest practitioner of CAR-T, Novartis also frequently invests in and cooperates with CRISPR gene editing companies, hoping to make breakthroughs in the field of tumor therapy. For example, one of the goals is to solve the rejection reaction caused by the surface antigen of allogeneic T cells, so that the transformed cells can be returned without obstacles. Once the wish is reached, the problem of CAR-T commercialization will be solved.
Secondly, in order to occupy the commanding heights of gene editing technology, China has relatively loose policy supervision, providing sufficient space for technological development . In July 2016, the Ethics Committee of West China Hospital in Sichuan approved the clinical trial study of Lu You team, becoming the world's first CRISPR clinical trial. At that time, Lu You said that the study was only to evaluate the safety of treatment, and it was difficult to determine whether it was effective or widely applicable in clinical practice. It can be seen that with the support of policies, Chinese medical institutions have the opportunity to implement more clinical trials to prove the safety and effectiveness, and are expected to take the lead in launching gene-edited cancer treatment programs.
In fact, gene editing technology is still being explored, modified and upgraded. It is hard to say that any gene editing technology today is fully mature. The CRISPR system was first discovered in bacteria. On January 30 , 2018, "Science" magazine stated that scientists have discovered more than 10 bacterial immune mechanisms, which are all potential molecular tools . When the research mechanism becomes more thorough, it may replace CRISPR and become a more reliable and easy-to-use tool. Therefore, in the future, gene editing technology will continue to innovate and bring more surprises to mankind.
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