BOOST · Backbone-Optimized OligonucleotideS for Therapeutics

Therapeutic oligonucleotides (ONs) have recently gained increasing importance as new drugs. While conventional drugs are limited to targeting proteins, oligonucleotides are able to target diseases upstream at the mRNA level. This specificity in combination with their easy design renders them highly valuable. Furthermore, their applications are limitless, involving treatment of so-called undruggable diseases. The bottleneck in the development of new therapeutic oligonucleotides lies in the efficient synthesis of modified ONs. Often, these modifications require multi-step syntheses and are laborious resulting in a time-consuming process of drug development. Additionally, these modifications often negatively impact physiological and biological properties. In our proposal, “Backbone-Optimized OligonucleotideS for Therapeutics” (BOOST), we outline a methodology for efficiently modifying oligonucleotides. Key to success will be the development of novel reagents capable of intercepting solid-phase oligonucleotide synthesis due to their high reaction rate. This will enable rapid evaluation of mono- and multiple-modified oligonucleotides to assess their physiological and biological properties. Furthermore, the introduction of multiple functionalities will become possible. BOOST will serve as a new platform for designing therapeutic antisense oligonucleotides (ASOs) and siRNA. As a proof of concept, we will evaluate the most promising modified oligonucleotides in biological settings.