FORCE: Delivering Oligos to Beat Rare Muscular Diseases

Myotonic dystrophy 1 (DM1) is a DNA triplet repeat disease. Patients with DM1 have a long number of DNA repeats of CTG which translates to a CUG repeat at the RNA level. The toxic RNA then aggregates, forming foci in the nucleus which leads to the sequestration of splicing factors and spliceopathy. The disease is then manifested in patients as myotonia, muscle weakness, cardiac arrhythmia, and pulmonary abnormality. 

It's Dyne Therapeutics’ aim to deliver transformative therapies for patients with rare muscle diseases like DM1 using oligonucleotide therapies. In this presentation, Timothy Weeden, Head of Platform Development at Dyne, walked us through the company’s FORCE platform which has been developed for the targeted delivery of oligonucleotides to the muscle. 

The FORCE platform consists of three components: a fragment antibody targeting the transferrin 1 receptor (TfR1), a clinically validated linker (val-cit), and payloads targeted based on genetic diseases. Dyne picked the TfR1 receptor due to its high expression and rapid turnover in muscle tissues. To avoid downregulation, and to ensure selectivity for TfR1 over its close homologue TfR2, Dyne went with a fragment antibody approach with cross-reactivity to Cyno and human TfR1. 

Weeden then discussed the preclinical models that Dyne used to test their candidate DYNE-101, these included DMSXL mice with CTG repeats and human TfR1 knock-in and a cynomolgus monkey model for toxicity and dose range studies.  

Preclinical efficacy models for DM1 and Duchenne muscular dystrophy (DMD) show that the platform can effectively target and degrade toxic RNA, correcting mis-splicing and improving muscle function. Furthermore, non-human primate studies, showed robust knockdown of target genes with no dose-limiting toxicities, supporting its potential for clinical use. 

In conclusion, Weeden showed that the FORCE platform was able to effectively deliver therapeutic oligonucleotides to muscle tissue. Their candidate DYNE-101 is able to reduce toxic RNA and correct splicing defects with a favourable safety profile preclinically. The therapy is now undergoing Phase I/II clinical trials.