Pathogens as well as host cells (e.g. damaged cells) can release nucleic acids, including RNA. Extracellular RNA can mediate cell adhesion and activate Factor XII in the intrinsic coagulation pathway. Degradation of RNA by wild type RNase 1 diminishes the ability of RNA to mediate adhesion or coagulation. Release of proinflammatory cytokines can also be triggered by RNA outside the cell, which can cause endothelial cells to down regulate wild type RNase 1.
Once inside the cell, RNA can trigger cytosolic and endosomal sensors that are involved in the innate immune system, which mediates response to pathogens as well as autoimmune disease. For example, the Toll Like Receptors (TLRs) includes endosomal TLR3, TLR7, and TLR8, which bind to various types of RNA ligands. TLR agonists have been in development for many years (e.g. FDA approved imiquimod). In recent years, the potential utility of TLR antagonists has been explored both in preclinical models as well as in early stage clinical trials for lupus and psoriasis. Additional downstream targets for these type I interferon responses include interleukin 1 receptor-related kinase 1 (IRAK1), interferon regulatory factors (IRFs), and interferon receptors.
Given the enzyme’s broad cleavage profile, increasing RNase 1 levels to remove extracellular RNA can impact a variety of these processes from adhesion to the type I interferon response. A variant of human RNase 1 called QBI-139 has been developed specifically to disrupt gene expression in cancer and has shown a strong safety profile in a Phase 1 clinical trial. Additional variants of RNase 1 have been developed with extended serum half-life and/or altered cell binding/uptake.
One class of these variants are site-specific PEG-EVadeTM RNase conjugates that were developed in collaboration with Professor Ronald Raines and his laboratory at the University of Wisconsin-Madison. Both in vitro and in vivo studies were done to explore these conjugates, and some of the results from this project are provided in the following references:
Site-specific PEGylation endows a mammalian ribonuclease with antitumor activity. Thomas J. Rutkoski, John A. Kink, Laura E. Strong, and Ronald T. Raines (2011). Pubmed
Human ribonuclease with a pendant poly(ethylene glycol) inhibits tumor growth in mice. Thomas J. Rutkoski, John A. Kink, Laura E. Strong, and Ronald T. Raines (2013).Translational Oncology 6, 392–397. Pubmed