FORCE? Platform: Bringing to Bear a New Era in the Treatment of Muscle Diseases and Beyond

Oxana Beskrovnaya , Ph.D.? Chief Scientific Officer?

Rare neuromuscular diseases remain one of the greatest challenges for modern medicine with limited to no treatment options. At the same time, advancement of our understanding of disease biology and genetic causation along with technological progress of nucleic acid therapeutic approaches opens up a unique opportunity to target the genetic bases of neuromuscular diseases and provide much needed therapies for affected individuals.??

The major obstacle for developing effective nucleic acid therapeutics such as oligonucleotides to modulate gene expression or splicing is breaking the barriers of delivery to muscle and central nervous system (CNS).???

This is where innovative delivery technology such as the FORCE platform can make a crucial difference. The FORCE delivery platform was developed by a strong and devoted team of scientific innovators at Dyne that I have the privilege to work with as Chief Scientific Officer.??

My scientific career in researching and developing therapies for rare genetic disorders began with a Howard Hughes Medical Institute fellowship in the lab of Dr. Kevin Campbell, who is now Professor and Chair of Molecular Physiology and Biophysics at the University of Iowa Carver College of Medicine. Joining this pioneering research in disease mechanisms of muscular dystrophies, I had an opportunity to investigate the function of dystrophin and dystrophin-glycoprotein complex in Duchenne muscular dystrophy (DMD), revealing for the first time the pivotal role of dystroglycan that was published in Nature.??

At Dyne, we continue to solve complex and challenging problems as a team united by the mission of breaking delivery barriers and translating our innovative therapies into potentially transformative clinical benefits for people living with genetically driven neuromuscular diseases.??

With the FORCE platform, we have now advanced clinical-stage programs for myotonic dystrophy type 1 (DM1) and DMD, while also priming a promising pipeline expansion into facioscapulohumeral muscular dystrophy (FSHD) and exploring its potential application in Pompe disease through early preclinical work.?

Why the FORCE Platform Matters??

Surpassing the barriers that hamper effective delivery of oligonucleotides to muscle has been an enormous scientific and medical undertaking. Muscle tissues have unique traits. They are extremely dense, thereby hindering deep penetration and distribution of therapeutics. Additionally, muscle cells may not readily absorb therapeutic agents, and this requires specialized delivery methods to achieve targeted and sustained effects.??

The FORCE platform overcomes these hurdles by leveraging the cell biology of the transferrin receptor type 1 (TfR1) to enable delivery of oligonucleotides and other therapeutic payloads into tissues relevant to disease pathology, such as the muscle and CNS.?

How FORCE Works??

FORCE consists of three components:?

1. An antigen-binding fragment antibody (Fab): this is the core of the platform, the element shared across all programs, carefully designed to bind to TfR1 without affecting the natural and essential functions of the receptor.?
2. A cleavable linker: this component connects the Fab and the payload. It was chosen because of its serum stability and clinical validation in multiple marketed antibody-drug conjugates.??
3. A therapeutic payload: this is the active portion of the platform, which needs to be designed to address the genetic cause of disease. We can attach the same Fab to chemically distinct oligonucleotide payloads such as gapmer antisense oligonucleotides (ASO), phosphorodiamidate morpholino oligomers (PMO), and small interfering (si)RNA. More recently, we were able to engineer the platform with an enzyme payload.?

What We’ve Achieved with FORCE?

Currently, Dyne has clinical programs for two investigational therapeutics: DYNE-101 for DM1 and DYNE-251 for DMD exon 51 skipping-amenable patients. In DM1, the genetic cause of the disease is spliceopathy, triggered by a CUG triplet repeat expansion within the mutant toxic DMPK RNA that is trapped within the nucleus. Here, we use an ASO as a payload because of its effectiveness at degrading RNA residing in the nucleus. In DM1 patients, DYNE-101 has shown robust muscle delivery and dose-dependent, consistent splicing correction and improvements in multiple measures of muscle strength and function.?

For DMD, we use an exon skipping PMO payload designed to correct exon 51-skip amenable mutations and restore dystrophin expression. In DMD patients, DYNE-251 has demonstrated substantial dystrophin restoration and functional improvements in multiple cohorts – promising steps forward toward an effective therapy for DMD.?

Our late preclinical development pipeline consists of DYNE-302 for FSHD, a disease that results from aberrant activation of the DUX4 transcription factor in muscle that leads to progressive wasting of skeletal muscles. For DYNE-302 we have selected an siRNA payload designed to effectively degrade DUX4 mRNA and prevent DUX4 protein expression. In June of this year, we demonstrated that DYNE-302 achieves robust and durable?DUX4?suppression and functional benefit in humanized mouse models of FSHD.?

Our work on CNS delivery and Pompe disease are very promising developments for Dyne and the FORCE platform. The opportunities to make a difference for patients are vast, and delivery of therapeutics to CNS via TfR1 is an exciting area of research and development across the biotech industry. Recent preclinical data in Pompe disease showed that the FORCE platform’s modularity extends beyond oligonucleotides, and that the platform is suitable for muscle and CNS delivery of enzymes such as alpha-acid glucosidase.??

Driving FORCE: Our Team and Mission??

The successes we have had so far with the FORCE platform would not have been possible without the fierce commitment and selfless dedication of my fellow “Dynamos” and the patients and families we are aiming to serve. We started with a small, dedicated team of scientists and have grown into a larger group, while keeping our mission at the core of everything we do. Our commitment to patients expands beyond the walls of Dyne. We have formed strong partnerships with the broader scientific community and have been eager to learn from them and apply these learnings to better serve our patients. By sharing our findings and inspirational science at various global forums, we hope to raise awareness of these devastating, underserved diseases and the communities that they affect with the goal of shortening diagnostic odysseys and, ultimately, being able to offer transformational therapies based on the power of the FORCE platform.??

As we move forward, we are encouraged by the versatility that the FORCE platform offers and we are more determined than ever to transform lives—not just for patients living with muscle diseases, but across a broader range of genetic disorders. Each advancement fuels our mission to deliver targeted, innovative therapies to those in need. With the FORCE platform, we’re not just shaping the future of medicine—we’re creating real possibilities for people who rely on these breakthroughs.?