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A team led by Robert W. Finberg, MD, has received funding from a new Defense Advanced Research Projects Agency (DARPA) program focused on delivering powerful defenses against public health and national security threats. The program—called the PReemptive Expression of Protective Alleles and Response Elements (PREPARE)—was conceived as a result of breakthroughs in the science of programmable gene expression and is aimed at developing medical interventions that temporarily and reversibly modulate the expression of protective genes to guard against acute threats from influenza and other ailments.
“Our goal is to make use of our own genes to prevent virus infection before it gets started,” said Dr. Finberg, the Richard M. Haidack Professor and chair and professor of medicine. “We believe that advances in modulating gene expression can be used to tune the human immune system to more efficiently activate and fight disease. That should lead to new ways to treat viruses, in particular the flu.”
The PREPARE program builds from the understanding that the human body has innate defenses against many types of health threats, but that it does not always activate these defenses quickly or robustly enough to block the worst damage. To augment existing physiological responses, PREPARE technologies would provide a programmable capability to up- or down-regulate gene expression on demand, providing timely, scalable defenses that are proportional to anticipated threats. Service members and first responders could administer these interventions prior to threat exposure or therapeutically after exposure to mitigate the risk of harm or death.
Finberg and colleagues were one of five teams selected to develop a range of new medical interventions that temporarily and reversibly modulate the expression of protective genes to guard against acute threats from influenza and ionizing radiation, which could be encountered naturally, occupationally, or through a national security event. The aim of their research is to identify novel host and viral target sequences, including long noncoding RNAs, which can be used to boost host resilience against influenza. The project will involve performing innovative CRISPR-based screens on cultured human cells, identifying critical host and viral factors using samples from human research subjects, and implementing a lung airway model.
“Researchers working within the PREPARE program seek to improve rates of survival and recovery in catastrophic scenarios for which reliable and scalable countermeasures don’t currently exist,” said Renee Wegrzyn, PhD, the PREPARE program manager, in DARPA’s announcement of the research.
Influenza persists as a perennial health threat despite the development of vaccines that help protect against predicted strains of circulating virus. The annual challenge of developing a new vaccine and the burdensome logistics of storing, transporting and distributing injectable vaccines make alternative protective strategies desirable.
Using programmable gene modulators, scientists hope to boost the human body’s natural defenses against influenza and weaken the virus’ ability to cause harm by directly neutralizing the viral genomes. If successful, these approaches would potentially protect against virtually all influenza strains—regardless of whether a virus is newly emergent or has developed drug resistance—and would provide near instantaneous immunity, in contrast to traditional vaccines.
