Development of Endosomal Escape Vehicles to Enhance the Intracellular Delivery of Oligonucleotides
Patrick Dougherty
Senior Scientist, Entrada Therapeutics
Biological therapeutics are highly targeted and potent but are limited in their ability to reach intracellular targets of interest. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for their delivery is the use of cell-penetrating peptides (CPPs). Canonical CPPs, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we have designed a family of proprietary cyclic CPPs that form the core of our Endosomal Escape Vehicle (EEV™) technology, which is capable of delivering covalently conjugated-cargo across all tissue types. To demonstrate the potential of our platform, we employed our EEV technology for the delivery of splice-modulating oligonucleotides and evaluated the EEV-oligonucleotide conjugates in preclinical models of Duchenne muscular dystrophy (DMD). EEV-oligonucleotide conjugates demonstrated durable exon skipping and broad dystrophin protein expression in target tissues such as skeletal and cardiac muscles. These results suggest the significant therapeutic potential of our EEV-oligonucleotides for neuromuscular diseases, as well as the broader application of our EEV platform for the delivery of intracellular therapeutics.
Patrick G. Dougherty obtained a B.S in Chemistry and Biochemistry from Florida State University (2013). He continued to The Ohio State University to receive his Ph.D. in Professor Dehua Pei’s group. After graduation, he joined Entrada Therapeutics, where he has focused on the development and application of the EEV platform for the delivery of intracellular biologics. His research interests are focused on the discovery and optimization of peptidyl therapeutics through combinatorial, medicinal, and computational chemistry.