When it comes to “gene editing”, most people still have the impression of the controversial “gene edited baby” a few years ago. As one of the important branches of CGT, gene editing is shining brightly together with popular therapies such as AAV, CAR-T, CAR-NK, TCR-T, and TIL.
Recently, the application for marketing of the world’s first CRISPR gene editing therapy was accepted. This means that if it can pass the marketing approval in Europe this year, the world’s first CRISPR-Cas9 therapeutic drug will be born within this year.
Gene editing technology is a technology that can change a specific DNA sequence in the genome, mainly divided into gene knockout, cell fusion technology and CRISPR/Cas9 technology. In recent years, gene editing technology has been widely used in the fields of clinical drug development, animal and plant breeding, gene therapy and food safety testing.
The Magical “Gene Scissors”
Gene editing, also known as genome editing or genome engineering, is an emerging and relatively precise genetic engineering technology or process that can modify specific target genes in the genome of an organism.Its basic principle is similar to the search, replacement or deletion in the word program, that is, after the DNA sequence of the host cell is artificially modified, the “editing” of a specific target gene segment-knockout/knock-in is realized, so as to change the host cell. genotype purpose.
Gene editing relies on genetically engineered nucleases, also known as “molecular scissors”, to generate site-specific double-strand breaks (DSBs) at specific locations in the genome, inducing organisms to undergo non-homologous end joining (NHEJ) or homologous end-joining (NHEJ) Source-derived recombination (HR) is used to repair DSBs because this repair process is error-prone, resulting in targeted mutations. This targeted mutation is gene editing.
In the early days, creating breaks at specific locations on the double strand of DNA was not an easy task.The original ZFN (zinc finger nuclease) has greatly promoted the genome targeted modification technology, but the labor load is large and the cycle is long; TALEN (transcription activator-like effector nuclease) has both the specificity and design of the recognition target. It has more advantages than ZFN, but it is more dependent on upstream and downstream sequences.
Until 2012, Jennifer A. Doudna, a professor at the University of California, Berkeley, and Emmanuelle Charpentier, a professor at Umea University in Sweden, discovered a family of endonucleases that cut double-stranded DNA breaks under the guidance of double-stranded RNA through in vitro experiments, revealing that CRISPR ( Clustered regularly interspaced short palindromic repeats)/Cas9 (endonuclease) system has great potential for RNA-guided gene editing. The following year, Feng Zhang, an Asian scientist born in the 1980s and an assistant professor at MIT, published a paper in which he improved and applied CRISPR/Cas9 gene editing technology to mammalian and human cells for the first time. This milestone technology is called “gene magic scissors”.
As a third-generation gene editing technology, compared with ZFN and TALEN, CRISPR-Cas technology uses RNA-DNA binding instead of protein-DNA binding to guide nuclease activity, which simplifies design, reduces cost, and improves accuracy. The scope of application is wider.
However, CRISPR/Cas9 still has certain off-target effects. In 2016, Liu Ruqian, an alumnus of Zhang Feng, developed a single base editor (Base Editor) in the laboratory, which can realize the base replacement of CT (or GA) without causing DNA double-strand breaks. Editing efficiency and safety, also reduces off-target effects, and is more suitable for ubiquitous point mutations.
After several iterations and improvements, today’s gene editing technology has been able to achieve efficient site-specific genome editing, showing great potential in gene research, gene therapy, and genetic improvement.
The market continues to heat up
At present, gene editing technology has been widely used in various fields: in the medical field, gene editing can treat genetic diseases such as leukemia, hemophilia, and muscular dystrophy by changing the expression of pathogens; in the agricultural field, gene editing technology can improve The performance of crops such as disease resistance and stress resistance yield; in the field of bioengineering, gene editing technology can produce specific proteins, antigens and drugs by modifying microorganisms; in the field of environmental protection, gene editing technology can be used to modify organisms, such as Use gene editing technology to transform resistant insects, thereby reducing environmental pollution caused by pesticides.
MarketsandMarkets report shows that the global genome editing market (including CRISPR, TALEN and ZFN) will grow from US$3.19 billion in 2017 to US$6.28 billion in 2022, with a compound annual growth rate of 14.5%.
The business model of gene editing companies is mainly to provide organelle gene editing contract technical services.In the industrial chain, biotechnology companies provide research funds to universities and basic research institutions and share patent rights with them. Pharmaceutical companies, scientific research institutions, and animal and plant product manufacturers invest in biotechnology companies to jointly develop new products.
Due to the early mastery of the research and development source and core underlying patents of gene editing technology, the leading gene editing companies in the world are currently dominated by European and American companies.
Among them, companies related to the above-mentioned CRISPR pioneer scholars are relatively well-known in the industry. For example, CRISPR Therapeutics, co-founded by Emmanuelle Charpentier, is already profitable. In 2021, CRISPR Therapeutics’ annual revenue will be US$915 million, a year-on-year increase of more than 1,271 times; net profit will be US$378 million, a year-on-year increase of 208.25%. Recently, CRISPR Therapeutics and Vertex’s marketing application for the CRISPR gene editing therapy exa-cel submitted to the European Medicines Agency (EMA) was accepted. After Zhang Feng, Liu Ruqian and others founded Beam Therapeutics after Editas Medicine, the multiple base editing therapy developed by them was also approved by the FDA in November last year.
In contrast, gene editing companies in my country started late, and the number of drugs/therapies entering the clinic is relatively small.Up to now, Boya Gene’s CRISPR technology edited hematopoietic stem cells Phase I clinical infusion has been completed for patients, and the CRISPR technology edited hematopoietic stem cells of Bangyao Biotech and Ruifeng Biotech have been approved for IND. In addition, leading domestic biomedical companies such as Hengrui Medicine, Kanghong Pharmaceutical, Huada Group, and Huahai Pharmaceutical have begun to lay out the gene editing market by establishing subsidiaries.
In September last year, Biocytogen, the “first gene-editing stock” in China, landed on the Hong Kong Stock Exchange, and launched IPO guidance for the Science and Technology Innovation Board at the end of last year. The first financial report after listing shows that Biocytogen’s revenue and gross profit have grown impressively, with a gross profit margin of 72.87%. This has also driven the domestic gene editing primary market to gradually heat up:According to incomplete statistics from TechNode, in the whole year of 2022, a total of 14 gene editing-related companies have obtained financing.Dozens of institutions including Sequoia Capital, IDG, Matrix Partners, and Legend Capital entered the market,The financing rounds are concentrated in the seed round~A+ round,The cumulative financing amount exceeds 2 billion yuan.
In terms of indications, CRISPR therapy at home and abroad currently takes the genetic disease β-thalassemia as one of the main directions.Due to a gene defect that cannot effectively produce mature red blood cells, this disease is clinically manifested as anemia, and traditional treatment methods rely on lifelong blood transfusions, while gene editing therapy can help patients effectively get rid of blood transfusions and vascular occlusion crises from the root genetic level.
“Fuzzy” red lines
Since the gene editing technology was reported, it has quickly become the focus of policy makers and academic circles around the world. The risks and obstacles of the application and promotion of gene editing in terms of policy regulation, technology ethics, and market response are gradually emerging.
Gene editing is irreversible, its consequences are unpredictable, and may lead to some ethical and moral issues, such as the separation of genes as social identities, and even the possibility of social evils. In order to improve the application of gene editing technology, it is necessary to explore the impact of genetic modification on human society in order to achieve a balance between technology and morality and ethics, so as to avoid excessive technological development.
For gene editing technology, there is currently no unified regulatory standard at home and abroad, and the relevant laws and regulations in many countries are relatively vague, especially the supervision of animal and human experiments for gene editing technology has not yet been clearly defined. In addition, there are also significant differences in the management policies of gene editing technology in different countries. Some countries prohibit the application of gene editing, while others restrict the use of gene editing.
As far as my country is concerned, the “Human Assisted Reproductive Technology Specifications” promulgated by the former Ministry of Health in 2003 has clearly stipulated that “genetic manipulation of human gametes, zygotes and embryos for the purpose of reproduction is prohibited”, but it does not restrict human embryos other than reproduction. Gene editing research, such as agricultural breeding, etc. The “Opinions on Strengthening the Ethical Governance of Science and Technology” issued by the Central Committee and the State Council regulate key areas such as gene editing technology, artificial intelligence technology, and assisted reproductive technology. The Ministry of Commerce plans to revise the catalog to restrict the export of cutting-edge biotechnology such as CRISPER gene editing technology and synthetic biology.
In terms of the market, gene editing technology is expected to bring huge economic and social benefits. However, due to the high initial R&D costs, complicated process and insufficient R&D funds of many enterprises, the marketization of gene editing is far away. The lag of policy and market consumers’ reluctance to “genetically modified” have also limited the market promotion of gene editing technology.
The gene editing industry has relatively high barriers. As CGT maintains a rapid growth trend and the demand of downstream pharmaceutical companies is increasing, gene editing will also play an increasingly important role.In order to better promote the development of gene editing technology, countries should build a sound policy environment and introduce targeted regulations, such as urging the revision of the “Measures for the Ethical Review of Life Sciences and Medical Research Involving Humans”. Scientists should also continue to research and explore more feasible solutions to optimize and promote the development and application of gene editing technology.
