Small Molecules That Target the RNAs That Cause Pulmonary Fibrosis and Polycystic Kidney Disease
Abstract
Any disease that affects military personnel affect our military readiness. Indeed, military service is associated with an increased risk to develop cystic kidney disease (CKD) and pulmonary fibrosis, two Fiscal Year 2019 Peer Reviewed Medical Research Program Areas of Encouragement. In a survey of 15,000 military personnel deployed to Iraq and Afghanistan, 69% reported respiratory problems, precipitating the creation of a database to track military personnel diagnosed with post-deployment chronic pulmonary disease, including lung fibrosis, and two programs, STAMPEDE18 and STAMPEDE II, to evaluate lung function pre- and post-deployment. Likewise, higher rates of CKD are observed in Veterans (1 out of 6) than the general population, and CKD has been linked to higher rates of vascular disease, diabetes, and cancer. Thus, understanding how to short-circuit disease processes with drugs would advance new therapeutic paradigms for these important diseases and will also make our military more prepared to deal with threats. Over more than a decade, the Disney Laboratory has focused on an unconventional target for therapeutic intervention, RNA. The vast majority of drug discovery efforts are focused on protein targets, despite the fact that a very small portion of the genome is translated into proteins (~1%-2%). Further, only ~15% of the human proteins are considered to be druggable, severely limiting therapeutic pipelines. The therapeutic modality of choice for RNA targets has long been antisense oligonucleotides (ASOs). Unfortunately, ASOs suffer from therapeutic liabilities including poor cellular and tissue permeability, and clinical trials of ASOs have been halted due to non-specific activation of the immune system and thrombocytopenia. Therefore, alternative strategies are required not only to study disease pathology but also for therapeutic development. We have therefore focused our efforts on designing drug-like compounds that bind and deactivate disease-causing RNAs. Indeed, we have developed highly potent inhibitors in patient-derived cells and animal models using innovative approaches. Our proposal tackles developing a new paradigm for the treatment of CKD and pulmonary fibrosis by targeting the RNAs that operate in the corresponding disease circuits for destruction. Our strategies are strongly supported by our published studies in which our strategy was applied to other disease-causing RNAs (cancer and neurological in origin) and validating preliminary data for the RNAs that cause CKD and pulmonary fibrosis. In the first approach, we will design lead drugs that bind the RNAs and directly cleave them, deactivating the disease circuit. Indeed, our preliminary data show that our carefully designed compounds can cleave the RNA that causes CKD in cells. Thus, we will optimize this lead drug to bind tightly and selectively to the RNA that causes CKD, without binding to other RNAs in a cell, and then remove it from the cell altogether by cleaving it. We will comprehensively study the optimal compound in an animal model of CKD. Likewise, we will apply this approach to the RNA that causes pulmonary fibrosis. We recently developed an innovative approach to use the body’s innate immune system to degrade selectively a disease-causing RNA. That is, the drug degrades its intended target in disease-affected cells; it has no effect on healthy cells. This approach, which we call RIBOTACs, could revolutionize how diseases caused by RNA are treated. We will therefore apply our RIBOTAC strategy to the RNAs that causes pulmonary fibrosis and CKD. Briefly, we will tether a lead small molecule that selectively targets the RNA that causes pulmonary fibrosis with a small molecule building block that activates a cellular protein that functions in the immune system by cleaving foreign RNAs. Usually, this protein is only activated when a cell encounters a virus. Our small molecule lead drug will activate the protein to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010728
Entities
People
- Luke L. Lairson
Organizations
- Scripps Research
- United States Army