The RNA Therapeutic Modalities Team sat down with Dyne Therapeutics, Head of Neuromuscular Research, Stefano Zanotti to find out more about the research he’s undertaking, as well as his involvement in the RNA Therapeutic Modalities Summit (agenda here: https://hubs.ly/
1. Please introduce yourself and your role at Dyne Therapeutics.
Stefano Zanotti, head of neuromuscular research at Dyne Therapeutics, a muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases.
In my role, I oversee a multidisciplinary research team focused on the preclinical development of treatments for genetically driven neuromuscular diseases. We are responsible for the progress of our preclinical programs, leading up to a nomination of a potential clinical candidate.
2. How can oligonucleotide therapeutics overcome limitations in delivery to muscle tissue?
Oligonucleotides have been a proven approach in targeting liver and CNS tissues where significant medicine can be delivered. Despite clear drug targets and well-understood biology, we still do not have effective therapies for muscle diseases. Dyne was founded with the goal of overcoming these historical limitations by advancing modern oligonucleotide therapeutics. Our proprietary FORCE™ platform utilizes the importance of Transferrin 1 receptor, or TfR1, which is highly expressed on the surface of muscle cells, as the foundation of our novel approach to deliver therapeutic payloads to muscle.
3. Can you describe how you are applying the FORCE platform to treat neuromuscular disease?
We have designed our proprietary FORCE platform using our deep knowledge of muscle biology and oligonucleotide therapeutics. Our therapeutics consist of three components: a proprietary Fab antibody, a clinically validated linker and an oligonucleotide payload. We engineered our proprietary Fab to bind to TfR1 to enable targeted delivery to skeletal, cardiac and smooth muscle. We selected the linker for our platform based on its clinically validated safety in approved products, its serum stability and its ability to release the therapeutic payload within the muscle cell. We attach the Fab and linker to a therapeutic payload that can be an antisense oligonucleotide (ASO), phosphorodiamidate morpholino oligomer (PMO), a small interfering RNA (siRNA) or a small molecule, that we rationally select to target the genetic basis of disease. The mechanism of FORCE delivery is designed to utilize the natural biology of TfR1. We do not use membrane destabilizing agents to enter the cell or to escape the endosome. Our in vitro and in vivo data validate our approach and demonstrate that FORCE displays a distinct pharmacokinetic and pharmacodynamic profile, with the potential for a wide therapeutic index.
4. What are your plans for expanding your portfolio to target new disease indications?
We are committed to serious muscle disorders. Our initial focus is on advancing our therapeutic candidates in myotonic dystrophy type 1, Duchenne muscular dystrophy (DMD), starting with Exon 51, and facioscapulohumeral muscular dystrophy. These are diseases with no or limited therapeutic options. We are also focused on addressing the broader DMD population and developing therapeutics for patients with mutations amenable to skipping other exons, including Exons 53, 45 and 44. We also believe the FORCE platform has potential in other areas such as additional rare skeletal muscle diseases, as well as cardiac and metabolic muscle diseases.
5. What are you most looking forward to at the RNA Therapeutic Modalities Summit?
I’m excited to present on the potential of our FORCE platform and its promising ability to overcome current limitations of muscle tissue delivery. Additionally, after spending the past few years attending conferences virtually, I’m looking forward to interacting in-person with the broader RNA therapeutic community.