RNA Therapeutics for Infectious Diseases: Viral Hemorrhagic Fever
Abstract
Overview: U.S. military members are frequently deployed to areas of the world with viral threats and emerging infectious diseases. Viruses that cause viral hemorrhagic fever (VHF) are a significant threat; well-known examples include Ebola, Marburg, Lassa, and yellow fever virus. VHF is characterized by fevers, sore throat, vomiting, rashes, abdominal pain, and joint aches and can have high mortality rates. Viruses that cause VHF are relatively understudied, and no U.S. FDA-approved vaccines and therapeutics for VHF are available. In the past, such viral pathogens have been infrequent in the U.S., but they are increasingly encroaching into new territories, placing U.S. citizens at increased risk for VHF. Some have pandemic potential and can be used for bioterrorism, and thus are considered a high priority. Oligonucleotide (oligo) drugs, namely small interfering RNAs and antisense oligos, are ideal for preventing and treating VHF. As international leaders in oligo drug development, we have platforms for designing and generating drugs that can be rapidly developed and dispensed to combat VHF worldwide. Target patient group: We will develop an oligo drug for treating VHF in U.S. military members and frontline workers. We also aim to use oligo drugs to prevent VHF in those who could be exposed to these viruses. Objectives: Our main objectives are to: 1. Identify host and viral factors required for VHF. We will explore how each is involved in the disease process. Our strategy is to pinpoint key common factors needed for disease development so that we can design advanced oligo drugs to prevent and treat all VHFs. 2. Develop oligo drugs to target host and viral factors to prevent and treat VHF and examine their safety and efficacy in a small animal model of VHF. 3. Advance a top candidate to pre-Investigational New Drug (IND) discussions with the U.S. FDA and provide an oligo drug platform that can be easily adapted for other pathogens. Potential Clinical Applications, Benefits, and Risks: The primary clinical application is the prevention and treatment of VHF. The benefits and risks are summarized below. Benefits: Oligo drugs are injectable, provide long-lasting protection, can be rapidly produced at a low cost, are stable at tropical temperatures (where VHF infections originate), and do not require refrigeration for storage. Because oligo drugs can be chemically modified, they can be formulated to direct them to specific tissues or to multiple organs that are the primary sites of infection. Unlike vaccines or antivirals, oligo drugs can simultaneously target both the virus and human genes that the virus hijacks for its own purposes. A receptor that a virus uses to enter human cells would be one such target. Oligo drugs are ideal as a quick-acting treatment following virus exposure because they work rapidly (within 12 hours). Once the sequence of a virus is known, advanced mapping tools can be used to design a virus-specific therapeutic within 48 hours. Manufacturers can scale up oligo drug production to treat millions of people within months of identifying new threats. Our team has already successfully designed oligo drugs for other viruses and diseases such as COVID-19, amyotrophic lateral sclerosis, and Huntington’s disease. Oligo drugs have multiple advantages, including an unprecedented duration of effect (up to 6 months following a single injection), a clean safety profile, and high specificity. Risks: A potential risk of oligo-based drugs is unwanted activation of the immune system. Our team is leading efforts on chemical modifications to oligo drugs to mitigate this risk. Timeline: In this 4-year project, we will identify key factors required for VHF disease, develop oligo drugs targeting these factors, optimize delivery to relevant tissues and cell types, and test our candidate oligo drugs in a relevant small animal model of disease. At the end of the 4
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310546
Entities
People
- Katherine A. Fitzgerald
Organizations
- United States Army
- University of Massachusetts Medical School