Description:
Immune System Activators that Induce Double-stranded RNA
Princeton Docket # 18-3436
Immunotherapy is becoming an increasingly popular cancer treatment strategy that harnesses the power of the patient’s own immune system. Researchers at Princeton University have developed synthetic molecules that derepress retroviral elements in the human genome and cause rapid activation of RNA decay by the OAS/RNase L branch of the interferon response. Importantly, RNase L is a prostate cancer suppressor that is encoded by the hereditary prostate cancer 1 allele. In addition, the OAS/RNAse L pathway is an effector system involved in BRCA1-mediated apoptosis. The technology used for activation of the OAS/RNase L pathway is inherently compatible with RNA/DNA delivery systems used in the art. Thus, it is a possible adjuvant in immunotherapies of infectious and neoplastic diseases. The researchers are currently addressing the mechanism of retroviral activation. They are interested in exploring deliverability and therapeutic action in cancer (prostate and breast cancer) by partnering with industry.
Applications
Adjuvant for immunotherapies targeting cancer
Self-dsRNA inducer in cancer cells that restricts cell proliferation
Advantages
Small molecules amenable to standard synthesis and delivery
Flexible chemical composition requirements facilitate modifications
The only rapid activator of retroviral elements in human cells described to date
Possibility of local delivery and lack of side effects due to interferon toxicity
Intellectual Property & Development Status
Patent protection is pending.
Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity.
The Inventors
Alexei Korennykh is an Associate Professor of Molecular Biology at Princeton University. He is interested in structural and cell biology of pathways mediated by dsRNA and by RNA-processing receptors that mediate innate immunity to viruses and bacteria, cell proliferation, tumor progression, obesity and response to stress caused by imbalance of protein folding. Dr. Korennykh received his BS degree in Chemistry at Moscow State University (Russia). During his PhD work with Joe Piccirilli at the University of Chicago (1999-2005), he focused on recognition of RNA and eukaryotic ribosomes by enzymes that stop translation via structure-specific modification of large ribosomal RNA. For his postdoctoral work (2006-2011), he joined the laboratory of Peter Walter at University of California, San Francisco (UCSF). At UCSF he worked on a signaling mechanism by which cells deal with protein misfolding. This mechanism is called Unfolded Protein Response and involves upregulation of hundreds of protein folding genes. In some eukaryotic cells, such as yeasts, the entire UPR program is controlled by a single receptor kinase/ribonuclease Ire1 in the membrane of endoplasmic reticulum (ER). Dr. Korennykh found that Ire1 is activated by assembling into a high-order complex, co-developed synthetic small molecule modulators of Ire1, and determined the crystal structure of this high-order complex with a synthetic small molecule modulator bound. This work received UCSF Dean's 2010 Postdoctoral Prize and served as the basis for two international patent applications. His PhD and postdoctoral work was supported by the Burroughs Wellcome Fund and by The Jane Coffin Childs Memorial Fund for Medical Research. Dr. Korennykh's current work focuses on structural biology of the OAS/RNase L axis of the innate immune system and is supported by NIH (R01), Princeton University Office of Technology Management, Sydney Kimmel Foundation, and Burroughs Wellcome Fund.
Alisha Chitrakar is a Ph.D. candidate in the laboratory of Professor Alexei Korennykh at Princeton University. She is interested in building novel tools for pathogen detection and deciphering molecular mechanisms of host immune responses to pathogens and cellular stress. As a graduate student, she has engineered a novel biosensor for detecting innate immune stress-linked second messenger 2’-5’oligoadenylate (2-5A). This biosensor has broad applications in disease diagnostics, immune modulator drug screens and in probing molecular mechanisms of innate immune responses. Currently, she is involved in understanding the molecular mechanisms by which interferon responses can be escaped by immune system activators. She has expertise in protein engineering, recombinant protein purification, RNA and cell biology.
Contact:
Laurie Tzodikov
Princeton University Office of Technology Licensing
(609) 258-7256 • tzodikov@princeton.edu
Catherine Ruesch
Princeton University Office of Technology Licensing
University Administrative Fellow
cruesch@princeton.edu