CirCode Bio: Pioneering circRNA Innovation to Build the Next-Generation mRNA Therapeutic Platform
In the central dogma of biology, RNA plays a crucial role in transmitting genetic information. As academic research continues to deepen, RNA has become a significant breakthrough for disease treatment due to its pivotal intermediary position, demonstrating immense potential for the development of therapeutics for various diseases.
Today, mRNA technology has demonstrated its robust therapeutic potential during the COVID-19 pandemic, thereby driving the development of the entire nucleic acid drug industry. In this field, mRNA is no longer the only technology capable of disrupting drug development models; more cutting-edge research findings and scientific technologies are emerging, with circular RNA (circRNA) garnering significant attention.
In 2021, two investment events brought circular RNA into the spotlight: U.S. startup Orna Therapeutics (Orna) announced the completion of a $100 million financing round, becoming the world’s first company to develop novel therapies using circular RNA technology; Laronde, a startup dedicated to developing eRNA (endless RNA), secured a $50 million Series A financing round, followed by an additional $440 million in Series B funding to support the development of its technology platform and new drug pipeline. Circular RNA thus rose to prominence overnight, emerging as another promising candidate sought by domestic investment institutions in the nucleic acid therapeutics sector.
Also in 2021, CirCode secured tens of millions of dollars in financing from investors including K2VC, Xianfeng Qiyun, Apricity Capital, Kunlun Capital, and Yifeng Capital, becoming the first startup in China to raise funds based on circular RNA technology.If 2021 was Year One for the translational application of circular RNA, then CirCode is one of the international pioneers in this technological field.
CirCode is an innovative biotechnology company focused on the development of circular RNA nucleic acid therapeutics. The company is committed to leveraging its proprietary circular RNA technology platform to build a globally leading drug development platform based on circular RNA systems.
CirCode boasts a robust founding team, with the “iron triangle” of core figures—Professor Wang Zefeng, Dr. Yang Yun, and Dr. Tang Chenxiang—endowing the company with the dual advantage of advancing both R&D and operations in tandem.
In terms of R&D, Professor Wang Zefeng and Dr. Yang Yun have been deeply engaged in the field of circular RNA for over a decade, achieving numerous breakthroughs that have laid a solid theoretical foundation for the establishment of CirCode. Professor Wang earned his Ph.D. in Biochemistry from Johns Hopkins University and completed his postdoctoral training at MIT. Upon returning to China, he served as Director of the Max Planck Institute for Computational Biology. With over 20 years of research experience in molecular and computational biology, he is recognized as a global leader in RNA splicing, translation, and transcriptomics. His seminal work has been published in top-tier international journals such as Cell, Molecular Cell, Cancer Cell, and Nature Methods.
Dr. Yang Yun holds a Ph.D. in Molecular Biology and Biochemistry from Zhejiang University and completed postdoctoral training in the Department of Integrative Biology at the University of California, Los Angeles (UCLA) and in the School of Pharmacy at the University of North Carolina at Chapel Hill. In the United States, Dr. Yang conducted academic research in the field of RNA under the supervision of Professor Wang Zefeng. With 15 years of experience in RNA research, Dr. Yang has made significant contributions to the study of RNA processing, translational regulation, and their applications.
The two researchers and their team have achieved numerous breakthroughs in the field of circular RNA (circRNA). Their most significant academic contributions include: In 2014, they reported the first-ever discovery of in vivo translation of circRNAs worldwide, thereby overturning the definition of circRNAs as non-coding RNAs and ushering in an era in which circRNAs serve as templates for encoding therapeutic proteins. In 2016, they provided a detailed elucidation of the translation mechanism of circRNAs, revealing the molecular mechanisms underlying in vivo circRNA translation, and conducted systematic work to optimize the efficiency of in vivo circRNA translation.
In addition to supporting R&D, the addition of Dr. Tang Chenxiang has significantly strengthened CirCode’s operational management capabilities. Dr. Tang boasts over a decade of experience in biomedical R&D, industrialization, and management. He earned dual bachelor’s degrees in Life Sciences and Economics from Tsinghua University and obtained his Ph.D. in Molecular Biophysics and Biochemistry from Yale University in the United States. His professional background, which includes serving as Assistant to the Chairman of SOHO China, Assistant to the President of Shanghai Bowei Biology, and CEO of Maijin Biology, a subsidiary of Hengrui Medicine, has endowed Dr. Tang with extensive expertise in corporate operations and management.
Dr. Chenxiang Tang, Chief Operating Officer of CirCode
Speaking of the original intention behind the establishment of CirCode, Dr. Tang Chenxiang stated, “The importance of basic scientific research lies in its ability to provide a theoretical foundation for addressing unmet medical needs. Circular RNA actually has the potential to offer patients highly effective treatment regimens in the future. Therefore, from our perspective, it would be a significant missed opportunity not to pursue drug development. We hope to combine academic research with commercial power to ultimately transform circular RNA into a series of products that truly benefit patients. Alleviating patient suffering is the core mission that drove us to establish CirCode.”
Before mRNA gained widespread recognition over the past two years, circular RNA, as a newer area of technological research, was neither well understood nor widely accepted. According to Dr. Chenxiang Tang, Professor Zefeng Wang and Dr. Yun Yang had already co-founded a circular RNA technology company in 2018, essentially at the same time as two comparable companies in the United States. However, investors’ lack of understanding of this technology caused setbacks from the very beginning of their entrepreneurial journey. It was only after the COVID-19 pandemic, when U.S. investors grew more receptive to circular RNA, that this technology gained an opportunity to enter the global spotlight, thereby also attracting favor from China’s investment community for CirCode.
Regarding the future development of circular RNA, Dr. Tang Chenxiang stated, “In fact, the technological ceiling for circular RNA can be infinitely high. Once the technology matures, it will be able to translate into various types of proteins and perform the same functions as mRNA, thus holding great potential to become the next generation of mRNA therapies.”
It should be noted that,Although mRNA technology is currently highly sought after, it has limitations such as limited stability, lack of tissue-specific expression, and immunogenicity. Circular RNA, the "dark horse," holds promise for addressing these limitations of mRNA one by one.
Dr. Tang Chenxiang introduced that, compared to linear mRNA, circular RNA is more stable. The instability of mRNA stems from the presence of its terminal ends; ubiquitous RNases in the environment pose significant challenges to various stages of mRNA research and development, manufacturing, formulation, and storage. Furthermore, its role as a messenger in the central dogma dictates that mRNA typically has a very short half-life after entering the human body.Circular RNA possesses inherent structural advantages; as a closed loop lacking free ends, it is less susceptible to recognition by the body’s RNA degradation machinery. This confers greater in vivo stability compared to mRNA, thereby extending its therapeutic window.“This means that circular RNA can extend the dosing interval by leveraging its advantage of sustained protein expression; if mRNA requires an injection every two to three days, circular RNA holds the promise of enabling dosing once every few months.”
In terms of tissue specificity, mRNA, as a core molecule situated at the center of the central dogma, is expressed by all cells upon encounter, thereby lacking tissue specificity. In contrast, circular RNA can be designed and optimized to achieve expression in specific tissues. Dr. Chenxiang Tang stated, “The tissue specificity of circular RNA will provide significant assistance in managing drug side effects.”By leveraging circular RNA, we can achieve highly efficient expression exclusively within specific cells; even if delivery issues result in its entry into non-target tissues, this specificity minimizes off-target effects in other cell types.”
Furthermore, mRNA exhibits strong immunogenicity, which presents a double-edged sword for its development as a therapeutic agent. On one hand, the innate immune response activated by mRNA facilitates subsequent antigen presentation; on the other hand, excessive activation of innate immunity can trigger severe immune reactions, leading to virus-like symptoms and adverse effects such as inflammation and even autoimmune diseases. Therefore, base modifications are often employed to reduce the immunogenicity of mRNA.
Regarding this point,Circular RNA exhibits very low immunogenicity even without nucleotide modifications. Therefore, compared to mRNA, circular RNA holds greater advantages for future drug development.
Even so, circular RNA technology still has a long way to go. Dr. Tang Chenxiang believes that research on circular RNAs is currently in its early stages, with technical challenges yet to be explored. First, as a nascent technology, the practical application of circular RNA therapies involves considerable uncertainty. Dr. Tang frankly stated, “The successful launch of a drug involves multiple stages, including early-stage R&D, clinical trials, and manufacturing and distribution. To date, many aspects of these processes remain unknown in the field of circular RNAs and require further validation.” Another challenge lies in the delivery of nucleic acid therapeutics: “It remains to be determined which delivery system is optimal for circular RNAs, an issue that continues to warrant exploration and resolution.”
Whether leveraging the advantages of circular RNA or addressing the current pain points and technical challenges associated with circular RNA technology, CirCode has made comprehensive preparations and achieved full mastery of key technological breakthroughs.
Leveraging the advantages of circular RNA, CirCode has established a systematic R&D platform to explore therapeutic modalities with enhanced potency and build the next-generation mRNA therapy platform.Currently,CirCode possesses proprietary design and circularization technologies, offering distinct advantages in addressing the two major challenges of circular RNA therapeutics: circularization manufacturing and efficient translation.
In the preparation of circular RNA, mRNA circularization faces a notable challenge: the process leaves behind a short residual segment known as a “scar sequence.” This sequence is artificially introduced to facilitate circularization and cannot be removed afterward. However, its presence can lead to certain adverse effects, making it challenging to design constructs that avoid incorporating scar sequences.
CirCode has already achieved a breakthrough in this regard,Currently, they are applying for the patent on a globally unique technology that leaves no residues after cyclization.“We are also willing to license the technology externally once patent protection is secured, sharing with the industry our globally optimal cyclization technology—characterized by residue-free sequences, high efficiency, and ease of scale-up—to foster a mutually beneficial ecosystem,” said Dr. Tang Chenxiang.
In terms of efficient translation, the CirCode team has accumulated long-term research achievements, achieving cumulative translation far exceeding that of linear RNA, as well as a certain degree of tissue-specific expression.Currently, the team has validated the low immunogenicity of circular RNA in mice and achieved high-efficiency expression of the target gene.
Regarding the future development of circular RNA, Dr. Chenxiang Tang is full of confidence. He believes, “Once circular RNA technology matures, it can be used for a wide range of applications, with the potential to even replace some existing therapies. Moreover, many rare diseases are actually caused by the deficiency of certain proteins. If the required protein is very large, expressing such high-molecular-weight proteins poses significant challenges for current therapeutic approaches—a hurdle that even gene therapy may struggle to overcome. Circular RNA, however, has the potential to break through this bottleneck, providing viable treatment options for diseases that currently lack effective therapies.”
Facing the boundless market potential of circular RNA technology,CirCode has been advancing its efforts in both vaccines and therapeutic products, exploring, screening, and strategically positioning its product pipeline, with the aim of validating its theoretical predictions through empirical trial data.
Regarding future plans, CirCode aims to advance its existing pipeline to the Investigational New Drug (IND) stage as soon as possible, verifying the safety and efficacy of its drug candidates through clinical trials. “Currently, no circular RNA therapy has entered human clinical trials globally, and CirCode hopes to achieve a breakthrough in this area. In terms of our technological accumulation, pipeline progression, operational management, and other dimensions, CirCode’s development level is on par with, or even leads in certain key aspects compared to, international counterparts.”
CirCode is committed to becoming a pioneer in the field of circular RNA therapeutics. We aspire to collaborate with industry peers to advance and strengthen circular RNA technology, fully realizing its therapeutic potential to benefit patients worldwide. “The path of pioneering is often arduous and lonely. We have already initiated deep collaborations with industry leaders, subfield experts, and suppliers of instruments, consumables, and services. We firmly believe in the importance of joining forces, leveraging complementary strengths, and achieving mutual growth. We look forward to the day when our products can address unmet medical needs for patients.”