PREPARE: PReemptive Expression of Protective Alleles and Response Elements

Pathogens with pandemic potential, toxic chemicals, and radioactive materials all endanger public health and pose a threat to national security. 

Despite investment in the development of medical countermeasures (MCMs) to address these threats, many existing MCMs suffer from limited applicability, insufficient efficacy, requirements for repeat dosing, lengthy and complex manufacturing processes, and logistically burdensome storage requirements. In many cases, unique threats require unique responses, setting up a “one threat, one MCM” paradigm. 

These limitations make it extraordinarily difficult to treat the large numbers of individuals who could be impacted by the outcomes of a natural disaster, accident, pandemic outbreak, or directed attack in a heavily populated area.

The PReemptive Expression of Protective Alleles and Response Elements (PREPARE) program aims to develop a new approach by identifying innate host genetic defenses against threats and developing novel MCMs that can quickly activate and modulate these genes to boost protection—without altering the underlying genetic code. 

The programmable, gene-modulating MCMs DARPA envisions are intended to provide timely and robust protection against a broad range of threats; however, within the PREPARE program, research teams will seek to demonstrate proof of concept by addressing three major threat areas: influenza infection, organophosphate poisoning, and exposure to gamma irradiation.

PREPARE researchers will apply new insights from the fields of genome editing and in vivo delivery to develop safe, programmable, and transient treatments that precisely tune the activity of protective genes to preemptively activate and strengthen a host’s intrinsic defenses. 

Work on the program will identify and validate protective genes; develop novel MCMs capable of specific and multiplexable control of endogenous protective genes; and create methods to enable tissue-specific, in vivo delivery of programmable MCMs to confer protection in healthy animal models for relevant durations. 

The integration of these aims will support a capability to generate programmable, gene-modulating MCMs with a path towards clinical translation.