◎Reporter Chen Xi and intern Yan Chen
Circular RNA is extremely stable in living cells and is a popular target for the treatment of human diseases.
Its application potential is very great, and it has opened up new ideas for the field of biomedicine.
Circular RNAs with well-defined functions can be used not only as biomarkers for the diagnosis of certain diseases, but also as therapeutic targets for certain important diseases, especially immune diseases and cancer, and are widely used in infectious diseases, rare diseases, The treatment of blood diseases and tumors has both research and application value.
A few days ago, Yuanyin (Beijing) Biotechnology Co., Ltd. (hereinafter referred to as Yuanyin Bio), which focuses on the development of new vaccines and multiple new therapeutic fields with international cutting-edge circular RNA technology, announced that it has successfully completed a series A financing of over 280 million yuan.
Today, circular RNA technology has become the focus of development for several companies.
The reason why circular RNA is favored by researchers and capital is inseparable from its own advantages.
Studies have found that although most endogenous circular RNAs cannot express proteins, they can perform various regulatory roles in cells.
At the same time, the structure of circular RNAs allows them to avoid recognition by the innate immune system and exonucleases.
Therefore, compared with linear RNA, circular RNA is more stable, the production process is relatively simple, the delivery efficiency is relatively high, and the advantages are obvious.
It has the incomparable advantages of linear RNA
"Circular RNAs are a special class of non-coding RNA molecules that are specifically expressed in cells and tissues and perform various regulatory functions. Unlike linear RNAs, circular RNAs have a complete circular structure, which can be protected from exonuclease At the same time, the structure of circular RNA can avoid being recognized by the innate immune system.” Wei Wensheng, a professor at the School of Life Sciences of Peking University, introduced that circular RNA is more stable and conservative than linear RNA, and it is not easy to degrade.
Circular RNA has become a research hotspot in the field of nucleic acid drugs due to its incomparable advantages such as more stability, higher antigen level and longer maintenance time, and relatively simple production process.
"In the past, people thought that circular RNAs had no translation function. However, recent studies have found that after construction, such as inserting IRES (internal ribosome entry site) elements and target protein sequences, circular RNAs can be translated in cells. target protein." Wei Wensheng said.
For example, in the development of the new crown circular RNA vaccine, researchers have constructed a sequence encoding the receptor binding domain (RBD) required by the new coronavirus to infect cells and a domain that helps RBD form trimers.
After being delivered into the cells, the circular RNA vaccine can express the RBD trimer with high immunogenicity, induce the body to produce strong cellular and humoral immune responses, and generate a long-term immune memory, so as to prevent the new crown The role of virus-induced COVID-19.
The circular RNA technology platform established by Yuanin Biotechnology can quickly develop vaccines based on virus sequences, which is also a major advantage of its response to virus mutation.
At the same time, the technology platform can also be widely used in related disease fields such as protein replacement therapy for genetic diseases, and the expected therapeutic effect can be obtained only by giving patients a lower dose of circular RNA drugs.
In addition, circular RNAs are extremely stable in living cells and are popular targets for the treatment of human diseases.
Its application potential is very great, and it has opened up new ideas for the field of biomedicine.
Wei Wensheng further explained that circular RNAs with well-defined functions can be used not only as biomarkers for the diagnosis of certain diseases, but also as therapeutic targets for certain important diseases, especially immune diseases and cancer, and are widely used in infectious diseases. , rare disease, blood disease, tumor treatment, both research and application value.
However, the development of circRNA therapeutics is still in the early preclinical stage, and only a few research teams are advancing circRNAs from the laboratory to industrialization.
Although companies in this field have not announced specific product pipelines, referring to the industrial layout of mRNA, the development of infectious disease vaccines, personalized tumor vaccines, immunotherapy, and protein replacement therapy is still the main focus of this field.
Deploy technology platforms and product pipelines one after another
Circular RNAs were discovered in the 1970s, and until recent years, with the development of next-generation sequencing and other technologies, various characteristics of circular RNAs have gradually emerged.
This new research field has also developed rapidly in a short period of time, and Chinese scientists have also actively explored this field.
For basic research, on May 17, a team led by Chen Lingling, a researcher at the Center for Excellence in Molecular and Cell Science (Institute of Biochemistry and Cell Biology), Chinese Academy of Sciences, published a circular RNA review in Cell.
This paper summarizes a series of application scenarios of circular RNA transformation, such as RNA aptamer, molecular sponge for miRNA and protein, antisense RNA, regulation of innate immune response in cells, protein translation carrier and disease-related molecular markers, etc. Further transformation and utilization of circular RNA provides new ideas.
In terms of drug molecular target research, on June 6, Lin Wenchu, a researcher at the High Magnetic Field Science Center of the Hefei Institute of Physical Science, Chinese Academy of Sciences, published a paper in Molecular Cancer, introducing circular RNA as a molecular sponge to simultaneously bind multiple miRNAs , and then regulate a single signaling pathway to participate in the occurrence and development of tumors.
The research results are expected to provide new molecular markers and therapeutic targets for small cell lung cancer.
In addition, in terms of vaccine development and preparation, on March 31, Wei Wensheng's group published a research paper on circular RNA vaccines online in "Cell".
The circular RNA vaccine based on the new coronavirus delta variant RBD prepared in this study has broad-spectrum protection against a variety of new coronavirus variant strains.
Dr. Tang Xiaodong, CEO of Yuanyin Bio, said that the promising prospect of circular RNA technology is also reflected in the financing of emerging companies.
Since 2021, the field of circular RNA has repeatedly received huge financing.
Among them, Orna Therapeutics has raised about US$100 million since its establishment in 2019, focusing on the development of in situ CAR-T therapy; while Laronde, which was established in 2017, raised about US$500 million, and plans to build an eRNA modular technology platform. Create 100 circRNA drugs within the next decade.
In China, the cutting-edge circRNA companies represented by Yuanyin Biotechnology have moved hand in hand with international companies to create unique circular RNA technology platforms, and have taken the lead in the world in some product pipelines.
According to reports, Yuanyin Biology first established a technical platform for the efficient preparation of high-purity circular RNA in vitro, and designed a circular RNA vaccine encoding the new coronavirus spike protein RBD for the new coronavirus and its variants.
The circular RNA vaccine has broad-spectrum protection against a variety of new coronavirus variants, and provides a reference for vaccine development and vaccination strategies against the current rapidly mutating new coronavirus.
It is reported that the project has completed the in vivo animal challenge experiment in rhesus monkeys and successfully achieved the proof-of-concept.
The research progress of this project also shows that my country is at the forefront of the world in key technical nodes such as circular RNA cyclization methods and purification schemes.
At the same time, through the circular RNA technology platform, Yuanin Bio has also carried out a multi-pipeline product layout in the fields of infectious diseases, autoimmune diseases, rare diseases and cancer prevention or treatment.
To achieve industrialization, it is necessary to optimize key links
mRNA (linear RNA) itself has particularities such as high difficulty in precise synthesis, easy degradation, and difficult preservation, which makes mRNA drugs face challenges in process control, engineering assurance, large-scale preparation technology, quality control and quality system.
Even so, with the spread of the new coronavirus, in 2020, two mRNA vaccines were quickly commercialized with the joint efforts of all walks of life.
Compared with mRNA, circular RNA has a more stable structure, simpler process, more flexible delivery, and lower production, transportation and storage costs, so its industrialization advantages are more obvious, and it is an ideal platform for the development of next-generation new drugs.
Although circular RNA has obvious advantages, its industrialization also faces many problems.
"If we want to achieve industrialization, we need to scale up the process in vitro. The key links include the optimization of in vitro transcription, cyclization, purification and other steps, and process control, engineering assurance, and quality control in the production process. Process exploration and process confirmation are required. process." Tang Xiaodong said that how to promote the development of the upstream supply chain by building a complete R&D and process system is also an important factor in accelerating the implementation of circular RNA technology.
Wei Wensheng pointed out that the current circularization method and purification strategy of circular RNA are still immature, and the impact of its potential immunogenicity on vaccine development is not clear.
Many unknown factors restrict the development and application of circular RNA.
Tang Xiaodong said that after this round of financing, Yuanyin Bio will accelerate the process of industrialization and accelerate the clinical application of innovative technologies through the joint efforts of scientists, entrepreneurs and people from all walks of life.