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기사원문 Rznomics Develops the World’s First RNA Editing Therapy: “TSR will be the Standard Treatment” Rznomics develops anticancer drug and rare disease therapies using the world’s first RNA editing platform, Trans-Splicing Ribozyme(TSR). Through a special track, the company aims to be listed on KOSDAQ market as early as this year, or next year at the latest. Seong-Wook Lee, CEO of Rznomics said, “TSR has a potential for expanding to a package-deal with asset and platform technology.” He added, “We will sign a licensing-out contract soon, and apply for a technology evaluation.” A Pioneer of RNA Editing Technology In 2017, Dr. Lee established Rznomics Inc., after 20 years of TSR research. Since 1994, he began researching TSR during his postdoctoral fellowship at Duke University Medical Center, one of the institutions initially developed and published TSR technology. At that time, he focused on RNA-based autoimmune disease therapeutics and gene therapy, which was a novel approach. The work was reported on the cover of Nature Biotechnology, January 1997. After then, he returned to Korea and joined Dankook University as a professor. Dr. Lee continued developing TSR in Korea but it was a challenge, because many scientists shifted their path to RNA interference (RNAi) research, which was newly discovered in the early 2000s. “When I developed TSR at the first time, it was not enough to verify its specificity and efficacy. Moreover, in vivo delivery systems required more study. In the late 2000s, I was finally able to achieve tumor-specific treatment data with animal models. Gene therapy using virus vector as delivery system was tested in the market, so it accelerated TSR development.” The R&D project was on track as Rznomics was established in 2017. Dr. Lee emphasized, “Not only the platform, but we will make a meaningful deal with our own asset based TSR technology. We’ve already organized the development system and clinical/pre-clinical Pipelines.” Safer than any other Gene Editing TSR technology is specifically designed to avoid direct DNA editing. It removes targeted RNA and then replaces it with therapeutic RNA; it demonstrates the possibility of dual function with a single substance. It also can be programmed to deliver customized drugs to the target gene. Depending on the indication, it utilizes proper viral vectors. Adenovirus is used for temporary treatment including cancer therapy, and adeno-associated virus (AAV) is used for one-shot genetic cure. TSR technology is frequently compared with CRISPR gene editing, one of the promising platforms in the gene therapy field. Although CRISPR therapy provides the correction of abnormal genes, it causes concerns that might be functioned at off-target permanently. At present, there is no approved in vivo gene therapy yet. Dr. Lee explained that TSR shows off-target effects rarely. “If we try to edit a specific part of RNA A, but RNA B works normally and will be produced in the cell. Even if TSR inadvertently targets RNA B, but any off-target effects are transient and limited.” RNAi therapeutics inhibit target RNA for treatment, but there is a limited option and the current delivery system can reach liver cells only. For that reason, most global RNAi pipelines target liver-related diseases and they have limited potential to expand the target indication to other oncology. Rznomic’s lead pipeline RZ-001 is in Phase 1b/2a trials for hepatocellular carcinoma (HCC) in the U.S. and Korea, and in Phase 1/2a for glioblastoma multiforme (GBM). The U.S. FDA has granted RZ-001 Orphan Drug Designation (ODD) and Fast Track program for both indications. Moreover, RZ-001 received approval for an Expanded Access Program (EAP) in GBM, allowing medication prior to official approval to the patients who have no approved treatment. Rznomics plans to enter a combination clinical trial with immunotherapy and already contracted to Roche and Celltrion for receiving Tecentriq and Vegzelma (Avastin biosimilar) for free of charge. Tecentriq and Avastin are the FDA-approved first-line therapy for HCC. Dr. Lee noted, “In preclinical studies, RZ-001 improved biomarkers associated with immunotherapy. The result encouraged our partners to pay attention to the potential of RZ-001.” The company is accelerating the development of rare disease therapeutics with TSR. Dr. Lee said, “Not only the cancer therapy, but TSR is also competitive for rare and incurable diseases treatment. It comes from the unique property of TSR, which appears one-source multi-effect. TSR regulates gene expression at the RNA level, exhibiting high specificity and efficacy without exogenous protein or intracellular mechanisms. It also has the potential to correct multiple mutations with a single enzyme, meeting medical unmet needs related to rare and incurable diseases.” Rznomics is building a pipeline RZ-004 for inherited retinitis pigmentosa (RP) treatment which is one of rare genetic disorders. RP is a progressive inherited degenerative disease leading to vision loss due to photoreceptor damage and it occurs in 1 in 3,500~4,000 people globally. 30% of autosomal dominant RP cases are caused by mutations in rhodopsin gene. Rhodopsin, pigment-containing sensory protein converts light into an electrical signal. More than 150 rhodopsin mutations have been identified so far, and each mutation can trigger serious eye disease including retinitis pigmentosa. Current therapeutic pipelines typically target individual rhodopsin mutations, limiting their applicability to less than 10% of Western patients; the clinical trial is suspended at the moment. It is notable that RZ-004 can target all rhodopsin mutations by replacing mutant RNA with normal RNA. Its proprietary engineering skills control the gene expression level according to the mutation level. There are no competitors in the market, so once the company passed Phase 2 clinical trial, then it can apply to Accelerated Approval Program. Rznomics has already received IND approval for RZ-004 in Australia and patient recruitment will begin within 2025. A New Circular RNA Platform To overcome limitations of current RNA platforms, Rznomics developed a novel circular RNA platform. Most RNA-based vaccines and therapeutics are based on linear RNA, which is vulnerable to Ribonuclease due to its open structure. Circular RNA, single-stranded RNA that forms a covalently closed loop, expresses high stability and resistance against Ribonuclease. Though it is still in early stages globally, this technology is spotlighted as a new platform to develop vaccines and therapeutics. Ribozyme-based circular RNA synthesis is more prevalent than purely chemical or enzymatic methods due to its efficiency and scalability. Ribozyme-based technologies rely on the Permuted Intron-Exon (PIE) approach, which has a limitation that PIE leaves unintended sequences in the final output. On the other hand, Rznomic’s circular RNA, based on the Tetrahymena group I ribozyme shows higher efficiency compared to existing methods. “Our circular RNA platform overcame limitations of the previous technologies. What is more important, it produces the equivalent or higher gene expression compared to PIE,” Dr. Lee mentioned. Top Priority: Recruiting Industry Experts When Dr. Lee started the business, his top priority was recruiting experts. “Fortunately, I’m working with top experts in each field. Thanks to them, I could handle pre-clinical and clinical development, financial operation which I’m not good at.” Seongwoo Hong, vice president of Rznomics, has over 20 years of business development experience in domestic and global pharmaceutical companies, successfully leading multiple IND filings and approvals. He is managing the entire development process, including RA, CMC. Seung-Ryul Han, Head of R&D Center, has researched TSR for a long time through his BSc, MSc, and PhD at Dankook University. As leading numerous R&D projects, he acquired a reputation as a specialist in TSR field. CFO Jong-sun Rim has over 13 years of experience at PwC Korea, supporting IPO preparations, internal control advisory, and financial consulting for both public and private companies. Making TSR technology a global standard, that is Dr. Lee’s vision. He emphasized, “TSR will become an essential tool for DNA and RNA editing industries. In special indications, it will be the standard treatment in the near future.” He is looking forward to commercializing therapeutics Rznomics researched and developed. “Within 10 years, we will build an in-house manufacturing system from initial research to GMP production. It will be the stepping stone that Rznomics grow as a global biopharmaceutical company.” RNA Editing Technology Emerges as a Novel Tool for Cancer Gene Therapy Published in Molecular Therapy – Nucleic Acids (Journal of the American Society of Gene and Cell Therapy) Title of the Study: Targeted Suicide Gene Therapy for Liver Cancer Based on Ribozyme-Mediated RNA Replacement Through Post-Transcriptional Regulation This study aimed to develop a novel gene therapy for hepatocellular carcinoma (HCC) using a ribozyme-mediated RNA replacement strategy, leveraging adenovirus-delivered Tetrahymena group I trans-splicing ribozymes. The therapeutic approach induces selective apoptosis in cancer cells by targeting human telomerase reverse transcriptase (hTERT) RNA, which is abundantly expressed in tumor cells, and replacing it with a suicide gene transcript. Post-transcriptional regulatory elements were introduced to enhance therapeutic specificity and minimize toxicity to normal hepatocytes. To confer tumor-specific cytotoxicity, the authors engineered the ribozyme to catalyze trans-splicing of hTERT RNA, replacing it with a transcript encoding Herpes Simplex Virus thymidine kinase (HSV-tk). Expression and stability of the therapeutic RNA were improved by incorporating splicing donor and acceptor (SD/SA) sequences and the Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE). Additionally, to restrict ribozyme activity to malignant hepatocytes, a target site complementary to miR-122a—a liver-specific microRNA—was added (miR-122aT), thereby suppressing expression in normal liver cells. The optimized ribozyme showed potent and selective cytotoxicity toward HCC cells in vivo. In intrahepatic multifocal HCC mouse xenograft models, the therapy significantly inhibited tumor growth. Preclinical toxicology and biodistribution studies demonstrated minimal hepatotoxicity, underscoring the safety and translational potential of this platform. These findings highlight ribozyme-mediated trans-splicing RNA replacement as a promising next-generation strategy for gene therapy in HCC, offering selective tumor targeting while sparing healthy liver tissue—an essential advancement over conventional approaches. This study was featured as a highlighted article in Molecular Therapy – Nucleic Acids, a leading journal published by the American Society of Gene and Cell Therapy (ASGCT). Rznomics’ TSR (Trans-Splicing Ribozyme) platform has garnered international recognition. It was identified as the first RNA editing technology to enter clinical development in the 2023 Nature Biotechnology RNA editing spotlight issue, and was cited by Nature in 2024 as one of only three RNA editing platforms to have progressed to clinical trials.