Hear from CMO Dr. Michelle Mellion: Spotlight on the EDO Platform

1. What are the key differentiators of the Enhanced Delivery Oligonucleotide (EDO) platform in comparison to competitor platforms developing similar therapeutics?

People have long recognized the potential effectiveness of phosphorodiamidate morpholino oligomers (PMOs) in treating rare neurological disorders. However, delivering oligonucleotides to target tissues has always been a challenge. A product of over a decade of research, PepGen’s proprietary EDO platform addresses the critical issue of PMO delivery and has demonstrated higher uptake of oligonucleotides to the target tissues in preclinical and healthy volunteer studies. By attaching a peptide to the oligonucleotide, in preclinical studies, we have achieved 25x more delivery into the cell and the nucleus compared to naked oligonucleotides. We believe higher penetration should correlate with clinically efficacious results.

Competitor oligonucleotide candidates rely on large antibodies or antibody fragments that depend on receptors to enter the cell. Once inside, they may become trapped in the endosome, with higher doses of these large molecules potentially required to overcome this challenge.

Due to their unique composition, we believe our EDOs can be more easily taken up by the cell, escape the endosome, and reach the nucleus – the site of action—all at a lower dose in comparison to competitors.

2. Could you elaborate on the delivery mechanisms utilized by the EDO platform to transport oligonucleotides into the nucleus? How important is delivering the oligonucleotide into the nucleus for therapeutic purposes?   

Our EDO platform uses proprietary technology to link a small peptide to the therapeutic oligonucleotide, enhancing the delivery of the oligonucleotide into the cell and nucleus. These small, positively charged peptides were designed based on our understanding of cell membranes and our knowledge of endosomes and endosomal escape. Our EDOs’ small size and hydrophobic core provides an advantage for endosomal escape.

The site of action for our RNA-based therapies is the nucleus. Delivering a therapeutic level of oligonucleotide to the nucleus is crucial for achieving meaningful clinical outcomes. Since our approach does not necessarily rely on receptors, and our molecule is small relative to competing therapeutic approaches, we believe our therapies can escape the endosome and have the potential to deliver an effective level of oligonucleotides into the cell and nucleus.

3. How flexible is the EDO platform in addressing a wide range of neuromuscular and neurological disorders?

The EDO platform is flexible, and we believe we can leverage this platform to potentially address the underlying cause of a wide range of neuromuscular and neurological disorders. We believe it also has the potential to address the underlying cause for other conditions. Our preclinical data supports that EDOs are effectively taken up by cells and can get to the site of action, the nucleus. They are not limited by their size or by receptor uptake. Given the efficient cellular uptake and small size of our EDOs, it is likely we will be able to deliver therapies at lower doses than competing therapeutic approaches. There is also the potential to explore the possibility of linking other targeted cargos to our peptide for delivery to tissues in disorders we may decide to explore in the future.