Rznomics Says Genetic Disease 'RNA Replacement Enzyme' 'Mutational Effect'

[ASGCT 2023] What are the main preclinical results of "RZ-004," a candidate for autosomal dominant retinal pigment degeneration.."It will be submitted to FDA IND at the end of this year."

Rznomics has unveiled a follow-up program following a trans-splicing ribozyme-based anticancer drug in the initial clinical development stage. Rznomics announced on the 23rd that it had confirmed the effect of editing mutation-independent RNA based "RZ-004" developed as a treatment for retinitis pigmentationosa (RP) at the American Society for Gene Cell Therapy (ASGCT 2023) in Los Angeles.

Rznomics announced the optimization of candidate materials for RZ-004 and non-clinical results at the ASGCT, and the presentation was conducted by Dr. Ji-hyun Kim, head of the genetic disease task at Rznomics. Rznomics will submit a clinical trial plan (IND) to the U.S. Food and Drug Administration (FDA) later this year to enter clinical trials. According to Rznomics abstract information, group I introns-based trans-splicing ribozyme, an RNA replacement enzyme, is developing treatments using an RNA replacement mechanism. RZ-004 removes the mutated rhodopsin RNA and operates as a mechanism to replace it with normal rhodopsin RNA and edit it.

RZ-004 was transferred to the eye via the AAV (adeno-associated virus) vector. Rznomics has discovered the most accessible rhodopsin RNA target site through RNA mapping in the ribozyme library. It has been confirmed that the most efficient RNA editing occurs in the uracil (U) base of RHO RNA 5' UTR. Rznomics also optimized ribozyme structures and sequences to increase the trans-splying specificity and efficacy of RNA replacement enzymes. Rznomics has identified candidates with the highest trans-splicing editing efficiency in the in vitro cell line, and with notable data, it has confirmed that various RHO RNA mutations are replaced by normal (WT) RHO RNA.

Rznomics delivered RZ-004 via the AAV vector to evaluate whether it actually affects the invivo function. Rznomics delivered RZ-004 to both eyes as a subretinal injection to the retinal pigment epithelial rat model (P23HRHOKI). As a result, it was confirmed that the dose-dependent ERG b-wave amplitude (amplitude) increased when RZ-004 was administered, unlike the control group. In addition, in molecular and cell-level analysis, P23H RNA in retinal tissue was efficiently changed to WTRHO, and the outer nuclear layer composed of photoreceptor cells mainly targeted by ribozyme was thickened.

Rznomics also showed an electric retinal potential (ffERG) reaction when the AAV-based RHO target ribozyme was injected under the retina in the pig model (TgP23HRHO pig), and confirmed that the outer nuclear layer was thickened. In other words, RZ-004 ribozyme inhibits photoreceptor degradation and maintains function in both mouse and pig disease models, confirming the possibility of development as a therapeutic agent. Rznomics added that it confirmed safety in primates. Rhodopsin mutant dominant retinal pigment degeneration targeted by RZ-004 is very demanding because there is no existing treatment, said Seong-wook Lee, CEO of Rznomics. "We will do our best to provide innovative treatment opportunities as soon as possible to patients suffering from vision loss."