SEONGNAM, South Korea — Rznomics Inc., a South Korea based biopharmaceutical company specialized in the development of RNA-based gene therapeutics, recently received Phase 1/2a IND approval from the U.S FDA in October 10th for its hepatocellular carcinoma (HCC) treatment called RZ-001 and thus has achieved an important milestone for the company and the RNA editing field. Being the first U.S. FDA-approved ribozyme-based RNA reprogramming approach to be evaluated in patients, RZ-001, a gene therapy approach utilizing the company's proprietary trans-splicing ribozyme-based RNA reprogramming and editing technology, is a replication-incompetent adenoviral vector that expresses an hTERT targeting ribozyme with multiple additional MoA to treat HCC patients. Rznomics also received IND approval of RZ-001 from the South Korean Ministry of Food and Drug Safety this June and already initiated a phase 1/2a clinical trial in Korea. Therefore, U.S. FDA approval allows Rznomics to start an international clinical study in HCC patients treating them with RZ-001 and therapeutic RNA editing.

The trans-splicing ribozyme is derived from the self-splicing Tetrahymena group I intron, which both recognizes and reprograms the target RNA into the therapeutic transcript of interest. Ribozyme-based RNA editing technology developed by Rznomics has unique features, differentiating it from other nucleic acid-based editing approaches, as follows: (1) A single RNA molecule is capable of both suppressing target RNA expression and simultaneously expressing a therapeutic RNA. Thus, no potentially antigenic proteins or cofactors are required. (2) Safety can be improved by selectively inducing therapeutic RNA expression only in cells/tissues where the target gene is expressed. (3) Therapeutic gene expression can be regulated proportionally to endogenous cellular target RNA levels. (4) Editing occurs at the RNA level, not the genomic level, thus eliminating concerns about genomic toxicity and eternal genome changes. (5) Indications with multiple mutation sites scattered throughout a target RNA can be edited with a single RNA designed to react upstream of all mutations and by replacing and editing large stretches of RNA. (6) Additional safety can be conferred by building control mechanisms into the ribozyme itself, without the need to modulate intrinsic cellular mechanisms or external proteins. 

More specifically, RZ-001 engenders effective anti-HCC activity by suppressing hTERT expression selectively in cancer cells, which over-express hTERT, and simultaneously inducing a cytotoxic effect by trans ligating an HSVtk-encoding sequence into the reprogrammed hTERT mRNA. Moreover, the result of such editing efficiently induces immune cell infiltrations into HCC tumors in preclinical animal models. ( The Phase 1/2a clinical trial will be a dose escalation/expansion study to assess the safety and tolerability of RZ-001 and to determine the most effective dose with the least toxicities of RZ-001 in HCC patients with no extrahepatic metastasis. 

"The translation of the first trans-splicing-based RNA editing approach into an FDA-approved phase 1/2a clinical trial is an exciting achievement and a critical milestone for the RNA editing field. I am very excited about Rznomics' preclinical progress on ribozyme design and gene delivery optimization. The advances have allowed them to create and now translate a promising therapy, RZ-001, into the clinic. I and the entire editing field are eager to learn if RZ-001 and mRNA reprogramming is safe and able to combat hepatocellular carcinoma in patients. Rznomics is clearly a leader at bringing novel editing strategies to cancer patients that desperately need innovative, breakthrough therapies," said Dr. Bruce Sullenger, Joseph, and Dorothy Beard Professor of Surgery at Duke University. Dr. Sullenger is a scientific advisory board member of Rznomics and the initial pioneer developing approaches to therapeutically edit RNA and DNA using RNA guided endonucleases (RGENs) such as the group trans-splicing I ribozyme..

 "It's a monumental achievement of Rznomics that RZ-001, the first trans-splicing ribozyme therapy at the front of our therapeutic pipeline, has successfully received the IND approval in both Korea and the United States. I am really grateful that RZ-001 earned the opportunity to potentially fulfill the unmet needs of HCC patients. Through the advanced development phase, I hope Rznomics can provide more new therapeutic options to patients suffering from intractable diseases. Rznomics will further expand our pipeline by targeting indications with highly unmet medical needs for which the unique characteristics of our platform technology may be the most competitively applied." said Dr. Seong-Wook Lee, CEO and founder of Rznomics.

In addition to the HCC, Rznomics is expanding the indication of RZ-001 to glioblastoma multiforme and planning to submit the IND this year. Also under development are ribozyme-based RNA editing treatments for Alzheimer's disease (RZ-003) and inherited retinal dystrophies, called Retinitis pigmentosa (RZ-004).