Codelivery of Small-Molecule Inhibitors to Enhance RNA-Encoded Antibody Production
Abstract
Topic Area: Emerging Infectious Diseases Effective countermeasures are needed to protect military Service members that risk first response during disease outbreaks or become targets of weaponized biological agents. Long-term medical countermeasures such as vaccines can take months or even years to reach the clinic. On the other hand, short-term preventive or therapeutic measures that provide immediate protection can provide the Warfighter time to respond to infectious disease threats and deploy effective countermeasures. A promising short-term preventive/therapy approach is the delivery of antibodies that target and neutralize disease-causing agents. The genetic signature of antibodies targeting specific pathogens can be encoded in a ribonucleic acid (RNA). This RNA message can then be administered to patients using nanoparticle vehicles, which carry the RNA to cells where the genetic code is translated to secrete the desired antibodies. Problem: A critical prerequisite for providing protection with antibodies is to generate a sufficient amount that can effectively neutralize the invading pathogens. Expressing a protective level of antibodies requires highly efficient RNA systems, such as those derived from viruses. However, the same viral machinery that is designed to replicate and amplify protein production in cells also activates inflammatory signals that work against RNA replication. The net result is suboptimal antibody production and a lack of effective protection from disease. Solution: In order to evade the inflammatory responses that shutdown antibody production, the proposed research aims to screen a large library of drug compounds that can temporarily and locally block the inflammatory signals. Lead compounds that effectively enhance protein production from RNA will be loaded on the same nanoparticle vehicle carrying the RNA, restricting delivery of these potent compounds to the same cells that carry the RNA. Innovation: The proposed research focuses exclusively on developing intramuscular (IM) injectable RNA-encoded antibodies to facilitate ease of administration for Armed Forces deployed in remote regions. Secondly, the research strategy focuses on leveraging the delivery vehicle to enhance expression. This approach provides for a universal platform that is independent of the genetic message encoded in the RNA. Successful demonstration of this platform technology will motivate development of thermostable formulations capable of carrying on the field in pre-filled injectors, providing Armed Forces effective countermeasures against potential bioterror threats.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010588
Entities
People
- Amit Khandhar
Organizations
- United States Army