Dr. Kotaro Nakanishi helps Drive City Therapeutics’ ambitious RNAi research

Columbus, OH –Kotaro Nakanishi, co-founder of City Therapeutics and The Ohio State University's 2023 Early Career Innovator of the Year, is leading the charge in advancing the company's RNA interference (RNAi) therapeutics pipeline, placing them at the forefront of innovation.  The company aims to begin clinical development of its lead program by the end of 2025 and plans to submit one to two new Investigational New Drug applications (INDs) each year starting in 2026.

Nakanishi, a professor in the College of Arts and Science’s Department of Chemistry and Biochemistry, is at the forefront of RNAi-based medicine, focusing on the engineering of next-generation small interfering RNAs. These groundbreaking treatments are designed to deactivate specific genes associated with diseases, effectively halting the production of harmful proteins. To maximize the effectiveness of these therapies, City Therapeutics is developing advanced delivery techniques to ensure that RNA molecules effectively target a diverse array of cells and tissues.

“As we advance into a new era of medicine, the work led by Dr. Nakanishi at City Therapeutics is a shining example of how research can lead to real-world solutions,” said Susan Olesik, divisional dean of Natural and Mathematical Sciences in the College of Arts and Sciences. “His vision underscores our commitment to advancing science for the benefit of patients everywhere.”

MicroRNAs are RNA molecules, about 22 nucleotides (nt) long, that don’t produce proteins but help regulate how genes work. They bind to messenger RNAs which are like blueprints for making proteins and can block them from being used. To function, microRNAs need to form a complex with proteins called Argonautes (AGOs). Humans have four types of these Argonautes (AGO1, AGO2, AGO3, and AGO4). It was thought that only AGO2 could cut mRNA, but Nakanishi’s team discovered that AGO3 also has this ability.

“The slicer activity of AGO3 was significantly lower than that of AGO2 when programmed with approximately 22-nt guide RNAs,” said Nakanishi.  “Upon reviewing the literature, we realized that no one had programmed AGOs with shorter guide RNAs (tinyRNAs), as it was widely accepted that miRNAs had to be around 22 nt. We then programmed AGO3 with shorter guide RNAs and observed competitive slicer activity when loaded with 14- or 15-nt specific tinyRNAs, which we named cleavage-inducing tinyRNAs (cityRNAs).  City Therapeutics was named after these cityRNAs.”

By leveraging the latest advancements in cityRNA-dependent RNAi, Nakanishi and his team are dedicated to developing innovative therapies for both emerging and established medical conditions. Their efforts aim to enhance the success rates of clinical trials, ultimately improving patient outcomes.

“Now, we are ready to dive into the sea of tinyRNAs, an unexplored realm,” Nakanishi said. “I am very excited to collaborate with City Therapeutics to explore the potential applications of cityRNAs.”

City Therapeutics is led by many of the creators of the first generation of RNAi therapeutics. Management team and board members include:

• Barry Greene, board member; CEO of Sage Therapeutics and former President of Alnylam Pharmaceuticals
• John Maraganore, PhD, co-founder and executive chairman; former/founding CEO of Alnylam Pharmaceuticals
• Robert Nelsen, co-founder and board member; managing director and co-founder of ARCH Venture Partners
• Ari Nowacek, MD, PhD, co-founder and SVP, corporate development; partner at ARCH Venture Partners
• Ron Philip, board member; CEO of Orbital Therapeutics and former CEO of Spark Therapeutics
• Sebastian Trousil, PhD, co-founder and chief operating officer; formerly at RTW Investments
• Tracy Zimmermann, PhD, CSO; former chief development officer of Generation Bio and former senior director, research at Alnylam Pharmaceuticals

Additional co-founders and advisors include:

• Mark Keating, MD, co-founder; former lead scientist at Alnylam Pharmaceuticals
• Yukihide Tomari, PhD, co-founder; professor in the Institute of Molecular and Cellular Biosciences at The University of Tokyo
• Hans-Peter Vornlocher, PhD, scientific advisor; senior advisor to Axolabs
• Phillip D. Zamore, PhD, co-founder; chair and professor, RNA Therapeutics Institute of UMass Chan Medical School and investigator, Howard Hughes Medical Institute; former co-founder of Alnylam Pharmaceuticals