High-throughput Oligonucleotide Production System - PROJECT SUMMARY/ABSTRACT Oligonucleotide-based therapeutics is an exciting and rapidly advancing field of research, spurred by the groundbreaking discovery of RNA interference (RNAi) by Professor Craig Mello, Nobel Laureate, at the University of Massachusetts Chan Medical School (UMass Chan). RNAi and antisense-based drugs have shown clinical efficacy and are expected to become a significant class of therapeutic modalities. Fourteen siRNA or ASO drugs have been approved, with many more in clinical development. The recent progress in chemically modified guides for CRISPR-based therapies has also generated significant excitement. Advances in oligonucleotide delivery to organs throughout the body, including liver, lung, central nervous system (CNS), muscle, and kidneys, has led a growing number of investigators at UMass Chan to apply their disease and target knowledge to develop transformative RNA-based therapeutics. The pharmacokinetic properties of oligonucleotides are strongly influenced by their chemical structures, emphasizing the importance of advanced modification patterns and design expertise. Unfortunately, academic investigators cannot readily access a large number of therapeutic-quality, chemically modified oligonucleotides to identify drug leads. The RNA Therapeutics Institute (RTI) at UMass Chan is widely recognized as a leading center in RNA chemical innovation and translational research. Leveraging our expertise in chemistry, informatics, and delivery, we seek to accelerate the development of innovative RNA-based technologies and therapeutics by establishing a high- throughput production capability to synthesize 10,000 complex therapeutic RNA leads. This will allow investigators to evaluate a large number of optimally modified oligonucleotides and identify the most potent sequence-chemistry configurations. We are therefore seeking funds through a High-End Instrumentation Grant to acquire the necessary equipment for high-throughput synthesis, purification, and quality control of chemically modified RNA. The requested funds will be used to purchase state-of-the-art equipment, including the Advion puriFlash XS520, Biolytic Dr. Oligo 192 XLc, Heated Pressure Chamber, Dr. Oligo Processor, Agilent 1290 Infinity II Preparative LC/MSD and 6230B Time of Flight (TOF) LC/MS, Metrohm Compact Ion Chromatograph (I.C. Flex), and Thermofisher SpeedVac SPD210. These cutting-edge instruments will allow us to efficiently synthesize, purify, and analyze large numbers of chemically modified RNAs. This acquisition will significantly enhance our basic and translational research programs, enabling the development of novel RNA- based therapies for Huntington's Disease (HD), amyotrophic lateral sclerosis (ALS), organ rejection, nonalcoholic steatohepatitis (NASH), and other diseases, including rare/orphan diseases. The equipment will support ongoing studies funded by 17 NIH grants and multiple grants from private foundations.
