DARPA kicking off four-year effort to leverage gene tuning to mitigate threats

The Defense Advanced Research Projects Agency (DARPA) plans to host an informational event on June 13 for those interested in participating in a new program that seeks to temporarily leverage the human body’s natural genetic responses to counter biological, chemical, and radiological threats.

DARPA’s Preemptive Expression of Protective Alleles and Response Elements (PREPARE) program aims to “tune” gene expression to temporarily improve the body’s natural defenses against biological, chemical and radiological threats. The four-year program will address four key areas: influenza viral infection, opioid overdose, organophosphate poisoning and exposure to gamma radiation.

“The human body is amazingly resilient,” Renee Wegrzyn, program manager of PREPARE, said. “Every one of our cells already contains genes that encode for some level of resistance to specific health threats, but those built-in defenses can’t always express quickly or robustly enough to be effective. PREPARE will study how to support this innate resistance by giving it a temporary boost, either before or after exposure, without any permanent edits to the genome.”

In a departure from current research into gene editing, DARPA’s PREPARE program requires that treatments preserve the human body’s exact genetic code while temporarily — and reversibly — modulating gene activity. This would be accomplished through cellular messages known as epigenome and transcriptome that transmit the genetic instructions of DNA within cells.

“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.

The PREPARE program will require researchers to identify which gene targets trigger desired responses, develop in vivo technologies capable of modulating the targets, and create cell- and tissue-specific delivery systems that direct programmable gene modulators to the correct areas of the body. DARPA’s overall goal is to establish an analogous platform that can be adapted to wide-ranging and evolving threats.

“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 antivirals.”

DARPA anticipates that research will mostly be conducted via computer, cell culture, organoid and animal models to establish proof of concept. The end goal is medical countermeasures approved for use in humans, however. Teams awarded DARPA funding will be expected to submit at least one final product to the Food and Drug Administration for regulatory review as an Investigational New Drug or for Emergency Use Authorization.