Codone Biotech: Seasoned Pharma Veterans Join Forces to Pioneer tRNA Therapeutics, Ushering in an Era of 'Broad-Spectrum' Gene Therapy?

In 1957, Francis Crick proposed the central dogma, which defines the flow of genetic information from DNA to proteins, and introduced for the first time the concept that an “adapter molecule” is required for the transfer of information from RNA to proteins. In 1965, Robert Holley first isolated this adapter molecule, namely transfer RNA (tRNA), and elucidated its sequence and approximate structure, for which he was awarded the 1968 Nobel Prize in Physiology or Medicine. In 1982, Chinese-American scholar Yuet Wai Kan published a paper in Nature, proposing that engineered suppressor tRNAs could be designed to treat genetic disorders such as β-thalassemia.

Although research on tRNA has spanned more than 60 years and the concept of tRNA-based therapy was proposed over 40 years ago, the field of tRNA therapeutics has remained remarkably “low-profile,” with few companies having established a presence in this area.“It is not that it was too ‘low-profile’ to be noticed, but rather that the engineering design of tRNA is quite complex and constrained by multiple technical limitations.”

Dr. Wei Dong, co-founder of Codon Biosciences, told VCBeat: “First, tRNA sequences are highly conserved, possess unique structures, and undergo extensive modifications. For a long time, there was no effective bioinformatics-guided design system for tRNAs, nor were there precise and effective analytical methods to determine the molecular architecture and biological consequences of specific tRNA modifications, thus hindering rational design and optimization. Furthermore, tRNA expression levels are very high, far exceeding those of the more familiar mRNA. Therefore, to achieve the optimal therapeutic window, the expression level of engineered tRNAs delivered via vectors must be sufficiently high yet appropriately regulated. Fortunately, these challenges have been addressed in recent years, sparking new momentum in the field of engineered tRNA therapeutics.”

It is also in the past few years that a number of biopharmaceutical companies focused on developing tRNA therapies have begun to emerge worldwide.It is reported that biopharmaceutical companies such as Codone Biotech, Tevard Biosciences, Shape Therapeutics, Alltrna, hC Bioscience, and ReCode Therapeutics have already established a presence in this field globally. These companies are backed by top-tier incubators and venture capital firms, including Flagship, Takeda Ventures, and ARCH Venture Partners, while multinational pharmaceutical company Vertex has also begun to explore this space.Following the surge in mRNA therapies, tRNA therapies may emerge as the next frontier in gene therapy.

Founded in 2022, Kedong Biopharma is a biopharmaceutical company focused on the research and development of suppressor tRNA (Suppressor-tRNA), dedicated to developing transformative therapies for severe diseases caused by premature termination codons (Premature Termination Codon).Dr. Wei Dong and Dr. Kong Lingjie, the two co-founders of Kedong Biology, are both veterans in the pharmaceutical industry with over 20 years of experience in biopharmaceutical R&D and management. Having known each other for nearly a decade as industry colleagues, they bring complementary expertise to their partnership: Dr. Kong’s industrial experience is primarily focused on early-stage R&D and CMC (Chemistry, Manufacturing, and Controls) production, while Dr. Wei has made significant contributions in clinical translation and corporate management.

The two founders first met in 2014, when they crossed paths at a Chinese association in the San Francisco Bay Area by chance. AndDr. Wei Dong and Dr. Kong Lingjie both returned to China during the nascent stage of gene therapy in the country, witnessing and driving the rapid development of this emerging industry in China., with frequent interactions over the years. After more than two decades of accumulation, the two PhDs joined Kedong Bio, bringing extensive R&D and industry experience as well as a shared pharmaceutical philosophy.

Prior to joining the company, Dr. Wei Dong led and managed the global clinical development—from Phase I through Phase III and regulatory submission—of more than ten innovative drugs at multinational corporations such as BioMarin, Elan, Johnson & Johnson, and Shire. His portfolio encompassed R&D projects in oncology, neurodegenerative diseases, autoimmune disorders, and orphan drugs for genetic conditions. After returning to China in 2018, Dr. Wei, a pioneer in advancing gene therapy in the country, served as CEO of Edigene, helping the startup evolve into an international, clinical-stage, multi-platform gene therapy company within four and a half years, andObtained the first clinical trial approval for a gene-editing therapy in China and initiated Phase I clinical trials.

“During my decade-plus tenure leading clinical innovation projects abroad, the majority ended in failure.” What left the deepest impression on Dr. Wei Dong was that all five Alzheimer’s disease projects he led at the time failed, including those in Phase III clinical trials. His doctoral supervisor was diagnosed with Alzheimer’s disease while Dr. Wei was working on these projects and ultimately passed away from the condition. “At that time, I was indeed extremely disappointed. I keenly felt the urgent need of patients and their families for these therapies, and I also felt that I had failed to live up to their trust.”

Dr. Wei Dong remarked, “It took me nearly three years to regain the confidence to return to clinical research. Pioneering work cannot succeed without learning from earlier failures. In fact, the mechanisms of action and product formulations of the two Alzheimer’s disease drugs approved by the U.S. FDA this year drew heavily on the experience and lessons learned from our own past failures.”The success of innovative drugs ultimately stands on the shoulders of giants; in many cases, entrepreneurs themselves become those giants., we should embrace this responsibility, while all of us aspire to achieve success by standing on the shoulders of giants, rather than merely becoming giants ourselves.“Science is science, and pharmaceuticals are pharmaceuticals. We must conduct a comprehensive analysis of the associated risks and work hand in hand with our partners and investors to blaze new trails.”

Dr. Lingjie KongIn the international pharmaceutical industry, he/she has held key leadership positions such as Deputy Chief Scientist/Deputy Director of R&D and Vice President at Merck & Co. (MSD) and the startup Applied Stemcell, with over 20 years of experience in biopharmaceuticals, gene therapy, and cell therapy.He has participated in the research and development of multiple drugs at Merck & Co., including Januvia^®Annual sales exceeded $6 billion; led the research and development of multiple gene therapy and cell therapy drugs, including advancing two gene therapy and cell therapy projects into Phase I and Phase II clinical trials in the United States, respectively.

After guiding Applied StemCell through its early-stage development, Dr. Kong Lingjie encountered a challenge. “In 2017, the company began product development, so Applied StemCell, as the sponsor company, sought out CDMOs in the United States. At that time, I"We approached two CDMOs with considerable experience in the field of gene therapy, only to be told that one had a 1.5-year waiting list and the other a two-year wait. Under time pressure, we had no choice but to partner with an emerging CDMO company; however, after 15 months of close follow-up, they ultimately failed to produce the product."

Dr. Kong Lingjie had long taken this matter to heart. Coincidentally, upon returning to China that year, he met with the Chairman and CEO of Suzhou Porton Biopharma. They engaged in extensive discussions about industry issues related to CDMOs. “At the time, they expressed their intention to establish a biological CDMO business. Having already been contemplating the idea of building my own CDMO team due to prior experiences, we quickly reached an agreement. I subsequently joined Porton Biopharma as Chief Scientific Officer (CSO), overseeing the management and development of the company’s CDMO services in the field of gene and cell therapy.”

Now, the two co-founders have reunited in Shanghai to establish an international biomedical R&D and translational team at Kedong Biopharma, driving innovation in the emerging field of engineered tRNA therapeutics. The company’s scientific advisory board is led by RNA expert and 2017 Nobel Laureate Professor Michael Rosbash, alongside Professor Nahum Sonenberg, an expert in protein translation; Professor Guangping Gao, a specialist in AAV gene therapy; and Dr. Gerald Cox, a senior executive in clinical development for rare diseases. Together, they support the company’s global innovative R&D and clinical translation efforts.

Among the frequent breakthroughs announced by the scientific and industrial communities in recent years, engineered tRNA therapies have gradually demonstrated advantages over traditional gene therapies, with suppressor tRNAs leading the way in this field.

Among the more than 10,000 monogenic hereditary diseases in humans, mutations in over 4,000 genes can directly cause disease or are significantly associated with disease; of these disease-causing gene mutations, 10%–15% are premature stop codons., directly causing premature termination of the translation of key proteins and resulting in loss of function. Engineered suppressor tRNA molecules can incorporate a specific amino acid at the premature termination codon (PTC), thereby mitigating the impact of the PTC on protein translation. Suppressor tRNAs targeting a specific stop codon have the potential to treat all diseases caused by such premature termination codons, regardless of the location of the genetic mutation, the affected gene, or the specific disease.

The development in this field reached its first tipping point in 2022.In March 2022, Professor Guangping Gao and Professor Dan Wang’s team from the University of Massachusetts published an article in Nature, providing the first in vivo proof-of-concept that a suppressor tRNA therapy could restore the production of full-length functional protein in a mouse model of Mucopolysaccharidosis Type I, a rare genetic disorder, for up to six months. VCBeat is now collaborating with these two professors’ teams on further research and development.

The remarkable progress gene therapy has made in clinical applications and industrialization in recent years has turned the concept of a one-time cure from science fiction into reality. However, since the genetic disorders primarily targeted are mostly rare diseases, commercialization faces enormous challenges; even sky-high prices struggle to ensure sustainability. A case in point is UK-based Orchard Therapeutics, which announced in 2022 that it would cease investment in a marketed gene therapy product. Although this product clinically cured every patient who received the treatment, only 19 patients underwent the therapy over four years, insufficient to sustain the company’s commercial infrastructure.

Dr. Wei Dong explained, “tRNA suppression therapy has the potential to overcome this commercialization bottleneck. Since there are only three stop codons,”In the future, it may be possible to treat 10%–15% of patients with hundreds or thousands of genetic disorders using only three distinct suppressor tRNA molecules, thereby alleviating protein truncation caused by premature stop codons.This approach to expanding indications is common in traditional small-molecule and large-molecule pharmaceuticals, but has not yet emerged in gene therapy due to the diversity of genes and mutations. Suppressor tRNA therapy may be the first ‘broad-spectrum’Gene therapy brings a ‘broad-spectrum’ solution for personalized and precision gene therapy.

Currently, Kedong Biology has established a tRNA optimization technology platform, a delivery tool development platform, and a clinical translation technology platform. The company’s pipeline is primarily based on adeno-associated virus (AAV) delivery, targeting pathological conditions in multiple organs affected by genetic diseases, with the aim of achieving a one-time curative effect.The company plans to identify its first preclinical candidate drug in 2024 and advance its first product into clinical trials in 2025,“We have selected multiple initial indications, for which there is a significant unmet clinical need in target organs among patients worldwide. We aim to leverage suppressor tRNA therapy to bring new treatment options and hope to these patients, as well as to those with additional indications in the future.”

tRNA is a critical component of the protein translation system and epigenetics, with its role in human health and disease becoming increasingly recognized. Regarding future development, Dr. Wei Dong and Dr. Kong Lingjie stated, “We are currently focused on accelerating the development of our suppressor tRNA pipeline, aiming to advance our first product into clinical trials by 2025. Meanwhile, we will leverage tRNA therapy as an opportunity, starting with the treatment of diseases caused by protein truncation, and develop more innovative therapies targeting the fields of protein translation and epigenetics in the future.”