DARPA’s Broad-Spectrum Antagonists For Editors, or B-SAFE, program aims to identify and optimize novel molecules that enable precise, tunable control of gene editing processes
May 28, 2024
The rapidly evolving field of advanced genome editing tools has enabled the ability to modify genetic material in a manner that is precise, rapid, cost-effective, and broadly accessible. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein (Cas) or CRISPR-Cas technologies represent one of the most widely adopted tools in the genome engineering toolkit, and its advancement has revolutionized the field of biotechnology and genetic engineering. However, concerns regarding the precision, specificity, and control of CRISPR-Cas systems remain.
One promising avenue to enhance safety, efficacy, and utility is the discovery or design of novel inhibitors which have the potential to obstruct and tune regulation of CRISPR-mediated and other genome editing tools by limiting unintended, off-target effects and enabling control of activity in time and space. The DARPA Broad-Spectrum Antagonists For Editors, or B-SAFE, program aims to develop platform technologies for highly potent inhibitors for multiple classes, types, and species of editors with enhanced activity, utility, and breadth of coverage. By harnessing advanced computational discovery capabilities such as deep learning, the program also seeks to develop a platform for rapid discovery and development of inhibitors of novel, emergent gene editor technologies.
“Previous DARPA investments in the Safe Genes program demonstrated discovery of potent inhibitors for a wide array1 of CRISPR-Cas technologies, and developed platforms for discovery of inhibitors of these systems2,3," said Dr. Shannon Greene, B-SAFE program manager. “The B-SAFE program seeks to leverage these and other efforts to develop tools for discovery, optimization, and validation of broad-spectrum inhibitors for gene editing technologies.”
If the 30-month B-SAFE program is successful, performers will demonstrate broad-spectrum, potent and durable solutions as outlined in the broad agency announcement. Speed – both from novel editor to candidate inhibitor discovery, and from novel editor to in vitro model – is also critical, as is inhibitor functionality for novel editors.
DARPA will assess novel inhibitor activity in vitro over the course of the program and a subset of top performing molecules will be selected for scale up at quantities sufficient for testing and evaluation by Department of Defense stakeholders. Performers will also engage with appropriate regulatory authorities to meet or exceed safety regulations. Teams may be required to meet with ethical, legal, and societal implications experts and ensure the research addresses any related concerns.
“In concert, DARPA is interested in exploring methods to rapidly discover inhibitor molecules for novel gene editing technologies beyond CRISPR-Cas systems to keep pace with the rapidly advancing field while promoting safe use and minimizing off-target effects.” added Greene.
A special notice is now available on SAM.gov.
[1] Marino et al., Anti-CRISPR protein applications: natural brakes for CRISPR-Cas technologies. Nat. Methods 2020, 17(5), 471-479.
[2] Maji et al., A High-Throughput Platform To Identify Small-Molecule Inhibitors Of CRISPR-Cas9. Cell. 2019, 177, 1067-1079.
[3] Lim, et al., A general approach to identify cell-permeable and synthetic anti-CRISPR small molecules. Nat. Cell Biol. 2022, 24, 1766-1775.