PReemptive Expression of Protective Alleles and Response Elements Program Information

The PReemptive Expression of Protective Alleles and Response Elements (PREPARE) program aims to create an integrated platform capability for generating prophylactic and therapeutic medical countermeasures (MCM) to combat biological, chemical, or radiological public health and national security threats. PREPARE MCMs will enable a potent, safe, and transient approach for modulating gene expression to bolster the body's natural defenses to limit the damaging and potentially fatal consequences of threats to warfighters, first responders, and civilian populations.

The PREPARE program seeks to provide an alternative to current MCMs that, while useful, are not sufficiently protective due to minimal efficacy, short half-lives, requirement for repeated administration, and difficulty in manufacturing and scaling. Given that every human cell contains genes that encode for some resistance to threats that may be encountered, PREPARE seeks to leverage and amplify innate resistances and develop novel MCMs that can activate and modulate endogenous protective genes-without altering the genetic code-to provide timely and robust protection against health threats. Proposers to the PREPARE program will leverage novel insights from emergent gene editing and genome engineering technologies to develop programmable gene modulators that are transient and reversible and do not alter primary DNA sequence or create DNA lesions in a host genome in any way. Thus the PREPARE MCMs will modulate the epigenome, transcriptome, or epitranscriptome to induce natural resistance to known or emergent threats, and/or enable the direct neutralization of viral genomes, prior to or immediately following exposure. PREPARE efforts will focus specifically on the development of disruptive platforms to generate novel MCMs to persistent public health and national security threats including influenza, opioid overdose, organophosphate poisoning, and exposure to gamma radiation.

Three program objectives will be pursued under the PREPARE program, including: (1) agnostic, genome-wide screens to identify and validate gene targets whose expression can be modulated to protect a host against health threats; (2) novel programmable gene modulators capable of transient, specific, and multiplexable control of endogenous protective genes; and (3) delivery platforms to enable cell- and/or tissue-specific, non-immunogenic in vivo targeting of programmable gene modulators to confer protection in healthy organisms for durations of time that are relevant for protection against threats. The integration of these aims will support a capability to generate programmable gene modulators that is not only relevant for public health and national security but also a viable candidate for clinical translation, commercialization and technology transfer. Throughout the program, teams will be required to engage with the U.S. Food and Drug Administration in preparation for Investigational New Drug or Emergency Use Authorization submission of a novel programmable gene modulation MCM by the end of the 4-year program. Proposing teams should include experts in animal models, bioinformatics, gene modulation, and gene editor delivery formulations to successfully complete in vivo capability demonstrations.