Benzinga | Sep 20, 2021 07:36AM EDT

Dyne Therapeutics Presents New In Vivo Data For Its Myotonic Dystrophy Type 1 Candidate Demonstrating Robust Splicing Correction During World Muscle Society 2021 Virtual Congress

Dyne Therapeutics, Inc. (NASDAQ:DYN), a muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases, is presenting new in vivo data during the World Muscle Society (WMS) 2021 Virtual Congress demonstrating the ability of its myotonic dystrophy type 1 (DM1) candidate, DYNE-101, to target the nucleus and achieve knockdown of toxic DMPK RNA, foci reduction and correction of splicing in muscle tissues in the hTfR1/DMSXL mouse model.

"DM1 is a spliceopathy, and in a novel hTfR1/DMSXL model, DYNE-101 demonstrated robust correction of splicing in the heart and skeletal muscles, as well as knockdown of toxic human nuclear DMPK RNA at a magnitude that has the potential to be disease-modifying. In addition, the subcellular fractionation data we generated reinforce that DM1 is a nuclear RNA-driven disease and that DYNE-101 effectively acts in the nucleus. We are also pleased that DYNE-101 was well tolerated in a non-human primate dose-range finding study," said Oxana Beskrovnaya, Ph.D., Dyne's chief scientific officer. "These findings further validate the FORCE(tm) platform as we drive our three programs toward the clinic, and we also look forward to presenting new in vivo data for our Duchenne program at the Muscle Study Group Annual Scientific Meeting in October."

DM1 is a rare, progressive, genetic disease caused by an abnormal expansion in the number of CTG triplet repeats in a region of the DMPK gene that causes toxic RNA to cluster in the nucleus, forming foci and altering the splicing of multiple proteins essential for normal cellular function. As a result of this altered splicing, people living with DM1 typically experience progressive weakness of skeletal, cardiac and smooth muscles. There are no approved disease-modifying therapies for DM1. DYNE-101 consists of an antigen-binding fragment antibody (Fab) conjugated to an antisense oligonucleotide (ASO) to enable targeted muscle tissue delivery with the goal of reducing toxic DMPK RNA in the nucleus, releasing splicing proteins, allowing normal mRNA processing and translation of normal proteins, and potentially stopping or reversing the disease.

The new data being presented during the World Muscle Society Congress were generated using an innovative hTfR1/DMSXL mouse model developed by Dyne that expresses the human transferrin 1 receptor (TfR1) and carries a human DMPK gene with more than 1,000 CTG repeats that represents a severe DM1 phenotype. In hTfR1/DMSXL hemizygous mice, the data demonstrated that human mutant DMPK RNA was trapped in the nucleus of muscle and that DYNE-101 acted within the nucleus to degrade toxic human DMPK RNA. In hTfR1/DMSXL homozygous mice, DYNE-101 delivered sustained reductions in toxic human DMPK RNA (49 percent) and foci area (49 percent) in heart tissue leading to splicing correction at 4 weeks. Similar results were observed in skeletal muscle, with DYNE-101 demonstrating toxic human DMPK RNA knockdown of 40 percent in the diaphragm, 49 percent in the tibialis anterior, and 44 percent in the gastrocnemius, along with correction of splicing in each muscle at 4 weeks.

While not a disease model for DM1, DYNE-101 was also evaluated in non-human primates where it was found to be well tolerated in a non-GLP toxicology dose-range finding study. No adverse findings or clinical signs of toxicity were seen after repeat ascending doses of DYNE-101, and no effects on body weight, kidney or liver function were observed.

The poster (EP.233) entitled, "The FORCE(tm) Platform Achieves Durable Knockdown of Toxic Human Nuclear DMPK RNA and Correction of Splicing in the hTfR1/DMSXL Mouse Model" is available in the Scientific Publications & Presentations section of Dyne's website.