Centyrin: siRNA conjugates – a novel modality for the treatment of human disease

Aro Biotherapeutics is a preclinical stage biotechnology company focused on the discovery and development of Centyrins, a new class of small, ultra-stable and highly soluble proteins engineered to specifically bind antigens with high affinity. Aro has created therapeutic lead candidates combining Centyrins specific for the transferrin receptor (CD71) with siRNAs that target Gys1, an enzyme responsible for glycogen production. CD71 Centyrin-Gys1 siRNA conjugates represent a new modality for the treatment of Pompe disease, a muscle glycogen storage disease. The CD71 Centyrin-Gys1 siRNA is highly effective at reducing Gys1 mRNA in vivo in an animal model of Pompe disease. Centyrin-drug conjugates therefore provide a means to deliver siRNAs to modulate genes once considered “undruggable”. We have shown that Centyrins enable the delivery and have extended exposure in early endosomes to facilitate delivery and endosomal release of siRNAs. Despite the long residence time in endosomes, utilizing the suite of Proimmune assays, we have shown that Centyrins have a low probability of eliciting an immune response in humans. Potential mechanisms for the low predicted immunogenicity will be discussed.

Steven Nadler, PhD, is currently Senior Vice President and Head of Discovery and Translational Research at Aro Biotherapeutics. Steve has more than 30 years of experience in drug discovery, development and translational research prior to Aro Biotherapeutics. As the former Executive Director and Head of Immunoscience, Immuno-oncology and Oncology Discovery Translational Research at Bristol-Myers Squibb, he was solely responsible for establishing the company’s Immunoscience and Immuno-oncology Discovery Translational Research group. During his tenure at Bristol-Myers Squibb, he took on roles of increasing responsibility in the autoimmune and oncology therapeutic areas, where he was instrumental in the discovery and development of five biologic and small molecules which entered the clinic for autoimmune diseases. He also led early clinical development for three of these biologics. Steve was an integral member of the teams which brought both ORENCIA® and NULOJIX® from discovery to the market. Steve received his PhD from the University of Texas at Houston, followed by postdoctoral studies at Yale Medical School. He has authored more than 80 publications and is co-inventor on over 10 patents.