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.