Bolstering the body’s defenses against public health, national security threats
The program will focus on four key health challenges as proofs of concept for what DARPA ultimately envisions as a generalizable platform that can be rapidly adapted to emerging public health and national security threats: influenza viral infection, opioid overdose, organophosphate poisoning, and exposure to gamma radiation.
“Each of these four threats are major health concerns that would benefit from disruptive approaches,” Wegrzyn said. “Seasonal flu vaccines, for example, are limited in that they try to hit a perpetually moving target, so circulating flu strains are often mismatched to vaccine strains. Programmable modulation of common viral genome sequences could potentially neutralize many more circulating viral strains simultaneously to keep up with moving targets. Combining this strategy with a temporary boost to host protection genes could change how we think about anti-virals.”
PREPARE requires that any treatments developed under the program have only temporary and reversible effects. In so doing, PREPARE diverges sharply from recent gene-editing research, which has centered on permanently modifying the genome by cutting DNA and inserting new genes or changing the underlying sequence to change the genetic code. Such approaches may cause long-lasting, off-target effects, and though the tools are improving, the balance of risk versus benefit means that these therapies are reserved for individuals with inherited genetic disorders with few to no other treatment options. In addition, some indications, including treatment of pain, may only require temporary solutions, rather than life-long responses.
The envisioned PREPARE technologies would provide an alternative that preserves the genetic code exactly as it is and only temporarily modulates gene activity via the epigenome and transcriptome, which are the cellular messages that carry out DNA’s genetic instructions inside cells. This would establish the capability to deliver programmable, but transient, gene modulators to confer protection within brief windows of time for meaningful intervention.
“Focusing only on programmable modulation of gene expression enables us to provide specific, robust protection against many threats at once, with an effect that carries less risk, is limited but tunable in duration, and is entirely reversible,” Wegrzyn said.
Success will hinge on developing new tools for targeted modulation of gene expression inside the body. Researchers must identify the specific gene targets that can confer protection, develop in vivo technologies for programmable modulation of those gene targets, and formulate cell- or tissue-specific delivery mechanisms to direct programmable gene modulators to the appropriate places in the body. Although the immediate program goal is to develop defenses against one of the four focus areas determined by DARPA, the ultimate objective of PREPARE is to develop a modular, threat-agnostic platform solution with common components and manufacturing architecture that can be readily adapted to diverse and emerging threats.
Research will be conducted primarily using computer, cell culture, organoid, and animal models to establish proof of concept. However, DARPA’s vision is to generate new medical countermeasures for future use in humans. As such, DARPA is working with independent bioethicists to identify and address potential ethical, legal, and societal issues.
DARPA says that by the end of the four-year program, the agency aims for each funded team to submit at least one final product to the U.S. Food and Drug Administration (FDA) for regulatory review as an Investigational New Drug or for Emergency Use Authorization. Throughout the program, teams will be required to work closely with the FDA to ensure that the data generated and experimental protocols meet regulatory standards.
DARPA will hold a Proposers Day on 13 June 2018, in Arlington, Virginia, to provide more information about PREPARE and answer questions from potential proposers. For additional information, visit: https://fbo.gov/spg/ODA/DARPA/CMO/DARPA-SN-18-45/listing.html.
